Pyrimidinone-containing compound, preparation method thereof, pharmaceutical composition and application thereof

ABSTRACT

Disclosed is a pyrimidinone-containing compound represented by formula I, a preparation method thereof, a pharmaceutical composition, and an application thereof. The pyrimidinone-containing compound of the present disclosure can be used as HIV-1 inhibitor and can be also used in the treatment of human immunodeficiency virus infection.

This application claims the benefit of Chinese Patent Application No.CN201810183285.5 filed on Mar. 6, 2018, the contents of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present disclosure pertains to the field of chemical synthesis andpharmaceutical technology, specifically relates to apyrimidinone-containing compound, and a preparation method,pharmaceutical composition and use thereof.

BACKGROUND ART

Acquired immunodeficiency syndrome (i.e., AIDS) is a disease caused byinfection of human immunodeficiency virus (HIV) in the body. Reversetranscriptase (RT) is the key enzyme that catalyzes the conversion ofviral RNA to DNA, and it is also a key target for the design ofanti-AIDS drugs.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have manyadvantages such as high efficiency, low toxicity, and good selectivityand are important components of current effective antiretroviral therapy(cART) for AIDS. Although the emergence of cART has greatly reduced themortality rate of AIDS patients and improved the quality of life, theexisting drugs cannot eliminate the virus, need to be taken for life andare accompanied by drug resistance and serious toxic side effects suchas dyslipidemia, insulin resistance, lipodystrophy, heart disease andother related diseases, which are the major reasons for the failure ofcART. At present, more than 60 types of NNRTIs have been reported, allof which bind to a binding pocket (NNBP) about OX away from the RTcatalytic center despite the divergence of their structures. Thisbinding pocket is highly flexible and makes the design of structurallydiverse NNRTIs possible.

Currently, there are five HIV reverse transcriptase inhibitors approvedby the FDA of U.S.A, namely: nevirapine, delavirdine, efavirenz,etravirine and rilpivirine. Because of the high variability of HIV-1virus, drug-resistant mutations such as L100A, H103N, Y181C andY181C+K103N have been produced after the first-generation NNRTIs(nevirapine, delavirdine) are widely used in clinic. Thesecond-generation NNRTIs (etravirine (ETV) and ripaverine (RPV)) havehigh inhibitory activity against a variety of drug-resistant strains,but their generally poor water solubility and membrane permeability leadto low bioavailability and increased oral dose, thereby causing toxicand side effects and cross-resistance. For example, etravirine hassevere skin allergic reactions, and ripaverine has toxic and sideeffects such as depression, insomnia, acute respiratory distresssyndrome, rash, and headache.

Therefore, the research of novel NNRTIs having high efficacy, lowtoxicity, broad-spectrum anti-drug resistance and good pharmacokineticproperties is still a hot field in the research and development ofanti-HIV drugs.

CONTENT OF THE DISCLOSURE

The technical problem to be solved by the present disclosure is toovercome the deficiencies of existing non-nucleoside HIV-1 reversetranscriptase inhibitors (NNRTIs) that generally have poor watersolubility and membrane permeability, resulting in low bioavailabilityand increased oral dose and further causing toxic and side effects andcross-resistance, thus providing a pyrimidinone-containing compounddifferent from the prior art, and a preparation method, pharmaceuticalcomposition and use thereof. The compound of the present disclosure canbe used as a HIV-1 inhibitor and can be used in the manufacture of amedicament for treating and/or preventing immunodeficiency virus (HIV).

The present disclosure solves the above technical problems through thefollowing technical solutions.

The present disclosure provides a compound represented by formula I, ora N-oxide, tautomer, optical isomer, hydrate, solvate, polymorph,pharmaceutically acceptable salt thereof or a prodrug thereof:

wherein:

A is S, O, NH or NCH₃;

R₁ is H, C₁-C₆ branched or straight chain alkyl, or C₃-C₆ cycloalkyl;

R₂ is H or halogen;

R₃ is H, C₁-C₁₂ branched or straight chain alkyl, C₃-C₆ cycloalkyl,C₆-C₂₀ aryl, C₂-C₁₀ heteroaryl, C₆-C₂₀ aryl substituted by one or more(e.g., 1-6, preferably 1-3 or 1-2) R_(3a), or C₂-C₁₀ heteroarylsubstituted by one or more (e.g., 1-6, preferably 1-3 or 1-2) R_(3b);wherein each of R_(3a) and R_(3b) is independently selected fromhydroxyl, nitro, halogen, amino, cyano, HOS(═O)₂—, CH₃S(═O)₂—, C₁-C₆branched or straight chain alkyl-S(═O)₂NH—, C₁-C₆ branched or straightchain alkyl, C₁-C₆ branched or straight chain alkoxy, C₁-C₆ branched orstraight chain alkylthio, C₁-C₆ branched or straight chain haloalkyl,when the number of R_(3a) or R_(3b) is more, then each R_(3a) or eachR_(3b) is the same or different.

α ring is cyclohexyl or phenyl, wherein the phenyl is substituted by nR₄ where each R₄ is the same or different, n is 0, 1, 2, 3 or 4; R₄ ishalogen, hydroxyl, cyano, nitro, amino, C₁-C₆ branched or straight chainalkyl, or C₁-C₆ branched or straight chain alkoxy.

In the present disclosure, when R₁ is C₁-C₆ branched or straight chainalkyl, then the C₁-C₆ branched or straight chain alkyl is preferablyC₁-C₃ branched or straight chain alkyl, further preferably isopropyl,n-propyl, ethyl or methyl;

when R₁ is C₃-C₆ cycloalkyl, then the C₃-C₆ cycloalkyl is preferablycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In the present disclosure, when R₂ is halogen, then the halogen ispreferably fluorine, chlorine, bromine or iodine, further preferablychlorine;

In the present disclosure, when R₃ is C₁-C₁₂ branched or straight chainalkyl, then the C₁-C₁₂ branched or straight chain alkyl is preferablyC₁-C₆ branched or straight chain alkyl, further preferably C₁-C₄branched or straight chain alkyl, more further preferably methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

when R₃ is C₃-C₆ cycloalkyl, then the C₃-C₆ cycloalkyl is preferablycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

when R₃ is C₆-C₂₀ aryl substituted by one or more R_(3a), then theC₆-C₂₀ aryl is preferably C₆-C₁₀ aryl, further preferably phenyl; theC₆-C₂₀ aryl substituted by one or more R_(3a) is preferably

When R₃ is C₂-C₁₀ heteroaryl substituted by one or more R_(3b), then theC₂-C₁₀ heteroaryl is preferably C₂-C₆ heteroaryl, further preferablypyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrimidinonyl, oxadiazolyl, pyridonyl or triazolyl.

In the present disclosure, when R_(3a) or R_(3b) is halogen, then thehalogen is preferably fluorine, chlorine, bromine or iodine;

when R_(3a) or R_(3b) is C₁-C₆ branched or straight chainalkyl-S(═O)₂NH—, then the C₁-C₆ branched or straight chain alkyl ispreferably C₁-C₃ branched or straight chain alkyl, further preferablymethyl, ethyl, n-propyl or isopropyl;

when R_(3a) or R_(3b) is C₁-C₆ branched or straight chain alkyl, thenthe C₁-C₆ branched or straight chain alkyl is preferably C₁-C₃ branchedor straight chain alkyl, further preferably methyl, ethyl, n-propyl orisopropyl;

when R_(3a) or R_(3b) is C₁-C₆ branched or straight chain alkoxy, thenthe C₁-C₆ branched or straight chain alkoxy is preferably C₁-C₃ branchedor straight chain alkoxy, further preferably methoxy, ethoxy, propoxy orisopropoxy;

when R_(3a) or R_(3b) is C₁-C₆ branched or straight chain alkylthio,then the C₁-C₆ branched or straight chain alkylthio is preferably C₁-C₃branched or straight chain alkylthio, further preferably methylthio,ethylthio, propylthio or isopropylthio;

when R_(3a) or R_(3b) is C₁-C₆ branched or straight chain haloalkyl,then the C₁-C₆ straight or branched chain haloalkyl is C₁-C₆ straight orbranched chain alkyl substituted by one or more halogen atoms, whereeach halogen atom is the same or different and can be on the same ordifferent carbon atoms; the C₁-C₆ straight or branched chain haloalkylis preferably C₁-C₃ straight or branched chain haloalkyl, furtherpreferably trifluoromethyl, difluoromethyl, or 1,2-difluoroethyl.

In the present disclosure, when R₃ is phenyl substituted by one or moreR_(3a), then the substituted is preferably mono-substituted ordi-substituted, the mono-substituted is preferably 3-substituted or4-substituted; the di-substituted is preferably 2,4-di-substituted or3,4-di-substituted.

In the present disclosure, when R₄ is halogen, then the halogen ispreferably fluorine, chlorine, bromine or iodine;

when R₄ is C₁-C₆ branched or straight chain alkyl, then the C₁-C₆branched or straight chain alkyl is preferably C₁-C₃ branched orstraight chain alkyl, further preferably methyl, ethyl, n-propyl orisopropyl;

when R₄ is C₁-C₆ branched or straight chain alkoxy, then the C₁-C₆branched or straight chain alkoxy is preferably C₁-C₃ branched orstraight chain alkoxy, further preferably methoxy, ethoxy, propoxy orisopropoxy.

In the present disclosure, when α ring is phenyl substituted by n R₄where each R₄ is the same or different, then n is preferably 2,preferably all R₄ are halogen or all R₄ are C₁-C₆ branched or straightchain alkyl; further preferably all R₄ are fluorine, or all R₄ arechlorine, or all R₄ are methyl; R₄ is preferably located in the2-position and 6-position of the phenly, or 3-position and 5-position ofthe phenyl.

In the present disclosure, when α ring is phenyl substituted by n R₄where each R₄ is the same or different, then n is preferably 2,preperably the two R₄ are C₁-C₆ branched or straight chain alkoxy,further preferably, the two R₄ can be linked together to form a ring,i.e., form an oxygen-containing heterocycle fused to the phenyl. Whenthe two R₄ form an oxygen-containing heterocycle fused to the phenyl,then the two R₄ preferably form an oxygen-containing 5-7 memberedheterocycle fused to the phenyl, e.g.,

In a preferred embodiment of the present disclosure, A is S.

In a preferred embodiment of the present disclosure, α ring is

In a preferred embodiment of the present disclosure, R₁ is H, methyl,ethyl or isopropyl.

In a preferred embodiment of the present disclosure, R₂ is H or Cl.

In a preferred embodiment of the present disclosure, R₃ is C₆-C₂ aryl,C₂-C₁₀ heteroaryl, C₆-C₂₀ aryl substituted by one or more (e.g., 1-6,preferably 1-3 or 1-2) R_(3a), or C₂-C₁₀ heteroaryl substituted by oneor more (e.g., 1-6, preferably 1-3 or 1-2) R_(3b).

In a preferred embodiment of the present disclosure, A is S, α ring is

R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is C₆-C₂₀ aryl, C₂-C₁₀heteroaryl, C₆-C₂₀ aryl substituted by one or more (e.g., 1-6,preferably 1-3 or 1-2) R_(3a), or C₂-C₁₀ heteroaryl substituted by oneor more (e.g., 1-6, preferably 1-3 or 1-2) R_(3b).

In a preferred embodiment of the present disclosure, A is S, α ring iscyclohexyl, R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is C₆-C₂ aryl,C₂-C₁₀ heteroaryl, C₆-C₂ aryl substituted by one or more (e.g., 1-6,preferably 1-3 or 1-2) R_(3a), or C₂-C₁₀ heteroaryl substituted by oneor more (e.g., 1-6, preferably 1-3 or 1-2) R_(3b).

In a preferred embodiment of the present disclosure, R₃ is C₆-C₂₀ arylsubstituted by one or more (e.g., 1-6, preferably 1-3 or 1-2) R_(3a),wherein the C₆-C₂₀ aryl is phenyl; R_(3a) is hydroxyl, halogen, C₁-C₆branched or straight chain alkyl, C₁-C₆ branched or straight chainalkoxy, C₁-C₆ branched or straight chain alkylthio, or C₁-C₆ branched orstraight chain haloalkyl.

In a preferred embodiment of the present disclosure, A is S, α ring is

R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is phenyl or phenylsubstituted by one R_(3a), wherein R_(3a) is hydroxyl, halogen, C₁-C₆branched or straight chain alkoxy or C₁-C₆ branched or straight chainalkylthio; the substituted is 4-substituted.

In a preferred embodiment of the present disclosure, A is S, α ring iscyclohexyl, R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is phenyl orphenyl substituted by one R_(3a), wherein R_(3a) is hydroxyl, halogen,C₁-C₆ branched or straight chain alkoxy or C₁-C₆ branched or straightchain alkylthio; the substituted is 4-substituted.

In a preferred embodiment of the present disclosure, A is S, α ring iscyclohexyl, R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is phenyl orphenyl substituted by one R_(3a), wherein R_(3a) is hydroxyl, F, Cl,methoxy or methylthio; the substituted is 4-substituted.

In a preferred embodiment of the present disclosure, the moiety

contained in the compound represented by formula I is

In the present disclosure, the compound represented by formula I ispreferably any one of the following compounds:

Compound Structure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

In the present disclosure, the compound represented by formula I ispreferably any one of the following compounds:

The present disclosure also provides a method for preparing the compoundrepresented by formula I, comprising carrying out an alkylation reactionof intermediate 6 and intermediate 7 in the presence of a base in asolvent;

wherein the definitions of A, n, R₁, R₂, R₃, R₄ and α ring are asdefined above, X is halogen.

In the present disclosure, the alkylation reaction occurs in accordancewith the mechanism of this type of alkylation reaction in the art, andconventional conditions and parameters for this type of alkylationreaction in the art can be employed.

In the present disclosure, X is preferably fluorine, chlorine, bromineor iodine, further preferably chlorine.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from DMF, THF, CH₃CN, dioxane and pyridine, more preferablyDMF.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the base can be a conventional base for thistype of reaction in the art, which is preferably one or more selectedfrom DMAP, Cs₂CO₃, K₂CO₃, Na₂CO₃, NaH and Et₃N, further preferablyK₂CO₃.

In the present disclosure, the amount of the base can be a conventionalamount for this type of reaction in the art, and the molar ratio of theintermediate 6 to the base is preferably 1:1 to 1:2, e.g., 3:4.

In the present disclosure, the molar ratio of the intermediate 6 to theintermediate 7 can be a conventional ratio for this type of reaction inthe art, which is preferably 1:1 to 1:1.2.

In the present disclosure, the reaction temperature of the alkylationreaction can be a conventional temperature for this type of reaction inthe art, which is preferably controlled between 20 and 80° C., e.g.,room temperature (20 to 25° C.).

In the present disclosure, the progress of the alkylation reaction canbe monitored by conventional detection methods in the art (e.g., TLC,HPLC or NMR), and the point where a raw material disappears or does notproceed to react is generally seen as completion of the reaction. Theduration of the alkylation reaction is preferably 3 to 24 hours, morepreferably 8 to 12 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises dissolving theintermediate 7 in part of the solvent, adding the base, then adding asolution of the intermediate 6 in the remaining part of the solventafter stirring, and reacting under continuous stirring.

In the present disclosure, after the completion of the alkylationreaction, the method for preparing the compound represented by formula Ipreferably comprises a post-treatment step comprising pouring thereaction solution into ice water, during which a white solid precipatesout; obtaining a crude product by filtering or extracting with ethylacetate; purifying the crude product by column chromatography orrecrystallization to obtain a pure product of the target compound.Wherein, the developing solvent for the column chromatography ispreferably a mixed solvent of ethyl acetate and petroleum ether, e.g.,ethyl acetate/petroleum ether=1:4 (v/v).

In the present disclosure, when α ring is cyclohexyl, then theintermediate 7 can be prepared by a method well known to those skilledin the organic chemistry field, Yan-Ping He, Jin Long, et al., Bioorg. &Med. Chem. 2011, 21, 694-697, third paragraph on page 695 can bereferred to for details (the contents of this reference are incorporatedherein by reference), specific synthetic routes are shown below:

wherein the definition of R₁ is as defined above.

In the present disclosure, when α ring is phenyl substituted by n R₄where each R₄ is the same or different, then the intermediate 7 can beprepared by a method well known to those skilled in the organicchemistry field, Maxim B. Nawrozkij, Dante Rotili, et al. J. Med. Chem.2008, 51, 4641-4652 can be referred to for details (the contents of thisreference are incorporated herein by reference), specific syntheticroutes are shown below:

wherein the definitions of R₁, R₄ and n are as defined above.

In the present disclosure, the compound represented by formula Ipreferably further comprises carrying out a halogenation reaction ofintermediate 5 with a halogenating agent in a solvent to obtain theintermediate 6;

wherein the definitions of R₂ and R₃ are as defined above, X is halogen.

In the present disclosure, the halogenation reaction occurs inaccordance with the mechanism of this type of halogenation reaction inthe art, and conventional conditions and parameters for this type ofhalogenation reaction in the art can be employed.

In the present disclosure, X is preferably fluorine, chlorine, bromineor iodine, further preferably chlorine.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from THF, CH₃CN, dioxane and pyridine, further preferablyCH₃CN.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the halogenating agent can be a conventionalhalogenating agent for this type of reaction in the art, which ispreferably one or more selected from Br₂, PBr₃, CBr₄, NBS, NCS, POCl₃and I₂, further preferably PBr₃.

In the present disclosure, the amount of the halogenating agent can be aconventional amount for this type of reaction in the art, and the molarratio of the intermediate 5 to the halogenating agent is preferably 1:1to 1:2, e.g., 1:1.2.

In the present disclosure, the reaction temperature of the halogenationreaction can be a conventional temperature for this type of reaction inthe art, which is preferably controlled between 0 and 85° C., e.g., 70to 85° C.

In the present disclosure, the progress of the halogenation reaction canbe monitored by conventional detection methods in the art (e.g., TLC,HPLC or NMR), and the point where a raw material disappears or does notproceed to react is generally seen as completion of the reaction. Theduration of the halogenation reaction is preferably 8 to 24 hours, morepreferably 0.5 to 3 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises dissolving theintermediate 5 in the solvent, adding the halogenating agent dropwiseunder an ice bath; proceeding with the halogenation reaction understirring after completion of the dropwise addition.

In the present disclosure, after completion of the halogenationreaction, the method for preparing the compound represented by formula Ipreferably comprises a post-treatment step comprising pouring thereaction solution into ice water, removing the solvent under reducedpressure, adjusting the pH to weakly alkaline with saturated NaHCO₃,filtering by suction, extracting the filtrate with ethyl acetate,combining the organic phases, washing the combined organic phase withsaturated brine and drying over anhydrous sodium sulfate, concentratingunder reduced pressure and recrystallizing to obtain the intermediate 6.Wherein, the recrystallizing is preferably performed with ethylacetate/petroleum ether (1:3, v/v).

In the present disclosure, the compound represented by formula Ipreferably further comprises carrying out a reduction reaction ofintermediate 4 in the presence of a reducing agent in a solvent toobtain the intermediate 5;

wherein the definitions of R₂ and R₃ are as defined above.

In the present disclosure, the reduction reaction occurs in accordancewith the mechanism of this type of reduction reaction in the art, andconventional conditions and parameters for this type of reductionreaction in the art can be employed.

In the present disclosure, the reduction reaction is preferably carriedout under the protection of an inert gas such as nitrogen.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from CH₃CN, THF, DMF, DMSO and dioxane, more preferably thesolvent is subjected to water removal treatment before use.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the reducing agent can be a conventionalreducing agent for this type of reaction in the art, which is preferablyone or more selected from NaBH₄, LiAlH₄ and KBH₄, further preferablyLiAlH₄.

In the present disclosure, the amount of the reducing agent can be aconventional amount for this type of reaction in the art, and the molarratio of the intermediate 4 to the reducing agent is preferably 1:1 to1:2, e.g., 1:1.5.

In the present disclosure, the reaction temperature of the reductionreaction can be a conventional temperature for this type of reaction inthe art, which is preferably controlled between 0 and 45° C., furtherpreferably room temperature.

In the present disclosure, the progress of the reduction reaction can bemonitored by conventional detection methods in the art (e.g., TLC, HPLCor NMR), and the point where a raw material disappears or does notproceed to react is generally seen as completion of the reaction. Theduration of the reduction reaction is preferably 2 to 12 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises adding the reducing agentin batches into a mixture of the intermediate 4 and the solvent under anice bath and nitrogen protection, proceeding with the reduction reactionunder stirring after the addition.

In the present disclosure, after completion of the reduction reaction,the method for preparing the compound represented by formula Ipreferably comprises a post-treatment step comprising adding saturatedaqueous ammonium chloride solution dropwise to the reaction solutionunder an ice bath to quench the reaction, filtering, extracting thefiltrate with ethyl acetate, combining the organic phases, washing thecombined organic phase with saturated brine, drying over anhydroussodium sulfate, concentrating under reduced pressure and recrystallizingto obtain the intermediate 5.

Wherein, the recrystallizing is preferably performed with ethylacetate/petroleum ether (1:3, v/v).

In the present disclosure, the compound represented by formula Ipreferably further comprises carrying out a halogenation reaction ofintermediate 3 with a halogenating agent in a solvent to obtain theintermediate 4;

wherein the definitions of R₂ and R₃ are as defined above.

In the present disclosure, the halogenation reaction occurs inaccordance with the mechanism of this type of halogenation reaction inthe art, and conventional conditions and parameters for this type ofhalogenation reaction in the art can be employed.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from CH₃CN, THF, DMF and dioxane.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the halogenating agent can be a conventionalhalogenating agent for this type of reaction in the art, which ispreferably one or more selected from NBS, NCS and NIS.

In the present disclosure, the amount of the halogenating agent can be aconventional amount for this type of reaction in the art, and the molarratio of the intermediate 3 to the halogenating agent is preferably 1:1to 1:6, e.g., 1:1.2.

In the present disclosure, the reaction temperature of the halogenationreaction can be a conventional temperature for this type of reaction inthe art, which is preferably controlled between 40 and 80° C., e.g., 60°C.

In the present disclosure, the progress of the halogenation reaction canbe monitored by conventional detection methods in the art (e.g., TLC,HPLC or NMR), and the point where a raw material disappears or does notproceed to react is generally seen as completion of the reaction. Theduration of the halogenation reaction is preferably 8 to 24 hours, morepreferably 10 to 15 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises dissolving theintermediate 3 in the solvent, adding the halogenating agent at roomtemperature, proceeding with the halogenation reaction under stirringafter completion of the dropwise addition.

In the present disclosure, after completion of the halogenationreaction, the method for preparing the compound represented by formula Ipreferably comprises a post-treatment step comprising removing thesolvent under reduced pressure, extracting with ethyl acetate, combiningthe organic phases, washing the organic phases with saturated brine anddrying over anhydrous sodium sulfate, concentrating under reducedpressure, and purifying the crude product by column chromatography toobtain the intermediate 4. The eluent for the column chromatography ispreferably ethyl acetate/petroleum ether (1:4, v/v).

In the present disclosure, the compound represented by formula Ipreferably further comprises carrying out a condensation reaction ofintermediate 2 with hydrazine hydrate in a solvent to obtain theintermediate 3;

wherein the definition of R₃ is as defined above.

In the present disclosure, the condensation reaction occurs inaccordance with the mechanism of this type of condensation reaction inthe art, and conventional conditions and parameters for this type ofcondensation reaction in the art can be employed.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from MeOH, EtOH, THF, dioxane, CH₃CN and H₂O, furtherpreferably EtOH.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the amount of the hydrazine hydrate can be aconventional amount for this type of reaction in the art, and the molarratio of the intermediate 2 to the hydrazine hydrate is preferably 1:1to 1:2.

In the present disclosure, the reaction temperature of the condensationreaction can be a conventional temperature for this type of reaction inthe art, which is preferably controlled between 30 and 85° C.

In the present disclosure, the progress of the condensation reaction canbe monitored by conventional detection methods in the art (e.g., TLC,HPLC or NMR), and the point where a raw material disappears or does notproceed to react is generally seen as completion of the reaction. Theduration of the condensation reaction is preferably 3 to 24 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises adding the hydrazinehydrate dropwise into a mixture of the intermediate 2 and the solvent atroom temperature, proceeding with the condensation reaction understirring and refluxing after the completion of the dropwise addition.

In the present disclosure, after completion of the condensationreaction, the method for preparing the compound represented by formula Ipreferably comprises a post-treatment step comprising cooling thereaction solution to room temperature, removing the solvent, extractingwith water and ethyl acetate, combining the organic phases, washing thecombined organic phase with saturated brine and drying over anhydroussodium sulfate, concentrating and recrystallizing to obtain theintermediate 3. Wherein, the recrystallizing is preferably performedwith ethyl acetate/petroleum ether (1:5, v/v).

In the present disclosure, the compound represented by formula Ipreferably further comprises carrying out a nucleophilic substitutionreaction of intermediate 1 with diethyl oxalate in the presence of abase in a solvent to obtain the intermediate 2;

wherein the definition of R₃ is as defined above.

In the present disclosure, the nucleophilic substitution reaction occursin accordance with the mechanism of this type of nucleophilicsubstitution reaction in the art, and conventional conditions andparameters for this type of nucleophilic substitution reaction in theart can be employed.

In the present disclosure, the solvent can be a conventional solvent forthis type of reaction in the art, which does not participate in orinterfere with the reaction, and the solvent is preferably one or moreselected from MeOH, EtOH, THF, CH₃CN, dioxane and toluene, furtherpreferably EtOH.

In the present disclosure, the amount of the solvent can be aconventional amount for this type of reaction in the art, which issufficient for completely dissolving the reactants and ensuring thesmooth progress of the reaction.

In the present disclosure, the base can be a conventional base for thistype of reaction in the art, which is preferably one or more selectedfrom DMAP, Cs₂CO₃, K₂CO₃, C₂H₅ONa, CH₃ONa, Na₂CO₃, NaHCO₃ and Et₃N,further preferably C₂HONa.

In the present disclosure, when the base is C₂HONa, the C₂H₅ONa can beproduced in situ using sodium metal and ethanol.

In the present disclosure, the amount of the base can be a conventionalamount for this type of reaction in the art, and the molar ratio of theintermediate 1 to the base is preferably 1:1 to 1:2.

In the present disclosure, the amount of the diethyl oxalate can be aconventional amount for this type of reaction in the art, and the molarratio of the intermediate 1 to the diethyl oxalate is preferably 1:1 to1:2.

In the present disclosure, the reaction temperature of the nucleophilicsubstitution reaction can be a conventional temperature for this type ofreaction in the art, which is preferably controlled between 20 and 80°C., e.g., room temperature.

In the present disclosure, the progress of the nucleophilic substitutionreaction can be monitored by conventional detection methods in the art(e.g., TLC, HPLC or NMR), and the point where a raw material disappearsor does not proceed to react is generally seen as completion of thereaction. The duration of the nucleophilic substitution reaction ispreferably 3 to 24 hours, e.g., 8 hours.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably comprises adding the diethyl oxalateto a mixture of the intermediate 1, the base and the solvent, andreacting at room temperature.

In the present disclosure, after completion of the nucleophilicsubstitution reaction, the method for preparing the compound representedby formula I preferably comprises a post-treatment step comprisingadjusting the pH of the reaction solution to 8 by addition of dilutehydrochloric acid, evaporating the solvent, extracting with water andethyl acetate, combining the organic phases, washing the combinedorganic phase with saturated brine, drying over anhydrous sodiumsulfate, filtering and concentrating.

In the present disclosure, the method for preparing the compoundrepresented by formula I preferably employs the following syntheticroute:

wherein the definitions of n, R₁, R₂, R₃, R₄, α ring and X are asdefined above, the specific reaction conditions and parameters for eachreaction of each step are as described above.

According to the preparation method described above, those skilled inthe art can employ the same principle and method to prepare eachspecific compound involved in the compound represented by formula I ofthe present disclosure.

The present disclosure also provides a use of the compound representedby formula I, or the N-oxide, tautomer, optical isomer, hydrate,solvate, polymorph, pharmaceutically acceptable salt theref of or theprodrug thereof as a non-nucleoside HIV-1 inhibitor, and thenon-nucleoside HIV-1 inhibitor is preferably a non-nucleosideHIV-1_(IIIB) inhibitor.

The present disclosure also provides a use of the compound representedby formula I, or the N-oxide, tautomer, optical isomer, hydrate,solvate, polymorph, pharmaceutically acceptable salt thereof or theprodrug thereof in the manufacture of an anti-HIV-1 medicament.

The present disclosure also provides a use of the compound representedby formula I, or the N-oxide, tautomer, optical isomer, hydrate,solvate, polymorph, pharmaceutically acceptable salt thereof or theprodrug thereof in the manufacture of a medicament for treating and/orpreventing human immunodeficiency virus (HIV) infection.

The present disclosure also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compoundrepresented by formula I, or the N-oxide, tautomer, optical isomer,hydrate, solvate, polymorph, pharmaceutically acceptable salt thereof orthe prodrug thereof, and at least one pharmaceutical excipient. The masspercentage of the compound represented by formula I, or the N-oxide,tautomer, optical isomer, hydrate, solvate, polymorph, pharmaceuticallyacceptable salt thereof or the prodrug thereof in the pharmaceuticalcomposition is 0.1% to 99.9%, and the mass percentage refers to the massof the compound represented by formula I, or the N-oxide, tautomer,optical isomer, hydrate, solvate, polymorph, pharmaceutically acceptablesalt thereof or the prodrug thereof in the total mass of pharmaceuticalcomposition. The sum of the mass fractions of the compound representedby formula I, or the N-oxide, tautomer, optical isomer, hydrate,solvate, polymorph, pharmaceutically acceptable salt thereof or theprodrug thereof and the pharmaceutical excipient is 100%. The selectionof the pharmaceutical excipient varies with the route of administrationand the characteristics of the action, and is generally a filler, adiluent, a binder, a wetting agent, a disintegrant, a lubricant, anemulsifier or a suspending agent.

The present disclosure also provides a method for treating humanimmunodeficiency virus (HIV) infection disease, wherein the methodcomprises administering a therapeutically effective amount of thecompound represented by formula I, or the N-oxide, tautomer, opticalisomer, hydrate, solvate, polymorph, pharmaceutically acceptable saltthereof or the prodrug thereof to a subject in need thereof.

Unless otherwise specified, the following terms employed in thedescription and the claims of the present disclosure have the followingmeanings.

The term “pharmaceutically acceptable salt” refers to a salt of thecompound of the present disclosure which is prepared by reacting thecompound of the present disclosure having a specific substituent with arelatively non-toxic acid or base. When the compound of the presentdisclosure contains a relatively acidic functional group, a baseaddition salt can be obtained by contacting the neutral form of thecompound with a sufficient amount of a base in a pure solution or asuitable inert solvent. The pharmaceutically acceptable base additionsalt includes a salt of sodium, potassium, calcium, ammonium, organicamine or magnesium or similar salts. When the compound of the presentdisclosure contains a relatively basic functional group, an acidaddition salt can be obtained by contacting the neutral form of thecompound with a sufficient amount of an acid in a pure solution or asuitable inert solvent. Examples of the pharmaceutically acceptable acidaddition salt include an inorganic acid salt, wherein the inorganic acidincludes, for example, hydrochloric acid, hydrobromic acid, nitric acid,carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate,dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid,phosphorous acid, etc.; and an organic acid salt, wherein the organicacid includes, for example, acetic acid, propionic acid, isobutyricacid, maleic acid, malonic acid, benzoic acid, succinic acid, subericacid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, andmethanesulfonic acid, etc.; and an salt of amino acid (e.g., arginine),and a salt of an organic acid such as glucuronic acid (referring toBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science66: 1-19 (1977), the content of which is incorporated herein byreference in its entirety). Certain specific compounds of the presentdisclosure which contain both basic and acidic functional groups can beconverted to any base or acid addition salt.

Preferably, through contacting a salt with a base or an acid in aconventional manner, then separating the parent compound, the neutralform of the compound is thereby regenerated. The difference between theparent form of the compound and its various salt forms lies in specificphysical properties, such as different solubility in a polar solvent.

“Pharmaceutically acceptable salt” used herein belongs to a derivativeof the compound of the present disclosure, wherein the parent compoundis modified by forming a salt with an acid or a base. Examples of thepharmaceutically acceptable salt include but are not limited to aninorganic acid or organic acid salt of a basic moiety such as amine, analkali metal salt or an organic salt of an acidic moiety such ascarboxylic acid, and the like. The pharmaceutically acceptable saltincludes conventional non-toxic salt or quaternary ammonium salt of theparent compound, such as a salt formed by a non-toxic inorganic acid oran organic acid. The conventional non-toxic salt includes but is notlimited to the salt derived from an inorganic acid and an organic acid,wherein the inorganic acid or organic acid is selected from2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid,ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonicacid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonicacid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolicacid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl,hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonicacid, nitric acid, oxalic acid, pamoic acid, pantothenic acid,phenylacetic acid, phosphoric acid, polygalactanal acid, propionic acid,salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamicacid, sulfanilic acid, sulfuric acid, tannin, tartaric acid andp-toluenesulfonic acid.

The pharmaceutically acceptable salt of the present disclosure can beprepared from the parent compound which contains an acidic or basicmoiety by conventional chemical methods. Generally, such salt can beprepared by reacting the free acid or base form of the compound with astoichiometric amount of an appropriate base or acid in water or anorganic solvent or a mixture thereof. Generally, anon-aqueous medium,e.g., an ether, ethyl acetate, ethanol, isopropanol or acetonitrile, ispreferred.

In addition to the salt form, the compound provided by the presentdisclosure also exists in the prodrug form. The prodrug of the compounddescribed herein is a compound that readily undergoes chemical changeunder physiological condition to be converted into the compound of thepresent disclosure. Additionally, the prodrug can be converted to thecompound of the present disclosure by a chemical or biochemical methodin vivo environment.

Some compounds of the present disclosure can exist in unsolvated orsolvated form, including hydrated form. Generally speaking, the solvatedform is equivalent to the unsolvated form, and both are included withinthe scope of the present disclosure. Some compounds of the presentdisclosure can exist in the polymorphous form or amorphous form.

The term “pharmaceutically acceptable carrier” refers to a carrier forany preparation or carrier medium which can deliver an effective amountof the active substances of the present disclosure, does not interferewith the biological activity of the active substances and has no toxicside effects on hosts or patients, representative carries includeswater, oil, vegetable and mineral, paste, lotion matrix, ointmentmatrix, etc. These matrices include suspensions, tackifiers, penetrationenhancers, etc. Their preparations are well known to those skilled inthe art of cosmetics or topical pharmaceuticals. For other informationabout carriers, Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott, Williams & Wilkins (2005), which is incorporated hereinby reference, can be referred to.

The term “excipient” usually refers to a carrier, a diluent and/or amedium required for the preparation of an effective pharmaceuticalcomposition.

For pharmaceuticals or pharmacological active agents, the term“effective amount” or “therapeutic effective amount” refers to an amountof a drug or medicament that is non-toxic but is sufficient to achievethe desired effect. For the oral dosage form in the present disclosure,the “effective amount” of an active substance in the composition refersto an amount required to achieve the desired effect when combined withanother active substance in the composition. The determination of theeffective amount varies from person to person, depending on age andgeneral condition of a receptor, and also on a specific activesubstance. The appropriate effective amount in a case can be determinedby those skilled in the art according to routine experiments.

Some compounds of the present disclosure can contain asymmetric carbonatoms (optical center) or double bonds. Racemic isomers, diastereomers,geometric isomers and single isomers are all encompassed within thescope of the present disclosure.

The compound of the present disclosure can have a specific geometric orstereoisomeric form. The present disclosure contemplates all of suchcompounds, including cis and trans isomers, (−)- and (+)-enantiomers,(R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers,and racemic mixtures and other mixtures, for example, enantiomer ordiastereoisomer enriched mixtures, are encompassed within the scope ofthe present disclosure. Substituents such as alkyl can have anadditional asymmetric carbon atom. All these isomers and mixturesthereof are encompassed within the scope of the present disclosure.

The diagrammatic representation of racemic isomer, ambiscalemic andscalemic or enantiopure compound of the present disclosure is fromMaehr, J. Chem. Ed. 1985, 62: 114-120, which is incorporated herein byreference. Unless otherwise indicated, the absolute configuration of astereocenter is represented by wedged and dashed lines. When thecompound of the present disclosure contains a vinyl double bond or othergeometric asymmetric center, unless otherwise specified, E, Z geometricisomers are included. Similarly, all tautomeric forms are encompassedwithin the scope of the present disclosure.

The chemical general formula involved in the present disclosure canexhibit tautomerism, structural isomerism and stereoisomerism. Thepresent disclosure includes any tautomeric or structural isomeric orstereoisomeric form and a mixture thereof, and they have the ability tomodulate kinase activity which is not limited to any form of the isomeror the mixture thereof.

Optically active (R)- and -isomers, (D)- and (L)-isomers can be preparedby chiral synthesis or chiral reagents or other conventional techniques.If an enantiomer of a compound of the present disclosure is desired,asymmetric synthesis or derivatization action of the chiral auxiliariescan be employed in preparation, in which the resulting diastereomermixtures are isolated, and the auxiliary groups are cleaved to providethe pure desired enantiomer. Alternatively, when a molecule contains abasic functional group (e.g., amino) or an acidic functional group(e.g., carboxyl), a salt of a diastereomer is formed with an appropriateoptical active acid or base, and then the pure enantiomer can berecycled after resolution on the salt of diastereomer by methods wellknown in the art. In addition, the isolation of an enantiomer and adiastereomer is usually realized by a chromatographic method, thechromatography method employs a chiral stationary phase, optionally incombination with a chemical derivatization method (e.g., an aminegenerates a carbamate).

One or more atoms constituting the compound of the present disclosurecan comprise an unnatural proportion of atomic isotopes. For example,the compound can be labeled by a radioactive isotope, e.g., tritium(³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C). All of these variations in theisotopic composition of the compound of the present disclosure, whetherradioactive or not, are encompassed within the scope of the presentdisclosure.

Unless otherwise specified, the reagents and raw materials used in thepresent disclosure are commercially available.

Unless otherwise specified, compounds are named manually or by ChemDraw®software, commercially available compounds use their vendor directorynames.

The above-mentioned preferred conditions can be arbitrarily combined toobtain preferred embodiments of the present disclosure in accordancewith common knowledge in the art.

The advantageous effect of the present disclosure is that the presentdisclosure provides a novel pyrimidinone-containing compound, and apreparation method, pharmaceutical composition and use thereof. Testshave proved that the compound of the present disclosure can be used as aHIV-1 inhibitor and has high use value. Specifically, the compound canbe used in the manufacture of an anti-AIDS medicament.

DETAILED DESCRIPTION OF THE EMBODIMENT

The following describes the present disclosure in detail withembodiments, but it does not impose any adverse limitation on thepresent disclosure. The present disclosure has been described in detailherein, and its specific embodiments are also disclosed. It is obviousto those skilled in the art that various changes and improvements can bemade to the specific embodiments of the present disclosure withoutdeparting from the spirit and scope of the present disclosure.

The experimental methods which are not specified in the followingembodiments are selected according to conventional methods andconditions, or according to product specifications. The raw materialscan be obtained from commercial sources, or prepared by methods known inthe art, or prepared according to the methods described herein.

The structures of the compounds were determined by nuclear magneticresonance (¹H NMR or ¹³C NMR) or mass spectrometry (MS), wherein NMR wasmeasured by Bruker AV-300 type nuclear magnetic resonance spectrometerwith deuterated dimethyl sulfoxide (DMSO-D₆) or deuterated chloroform(CDCl₃) as the solvent and TMS as the internal standard.

Preparation Example 1: Preparation of the Target Compound I

The synthetic route of the target compound I-1 is shown below:

Step (1): Preparation of Ethyl 2,4-dioxo-4-phenylbutyrate (Intermediate2-1)

40 mL of ethanol was added into a 200 mL round-bottom flask, followed byaddition of sodium (2 g, 0.083 mol) in batches under stirring at roomtemperature. After the above mixture cooled to room temperature,acetophenone (5 g, 0.042 mol) was added, followed by addition of diethyloxalate (7.4 g, 0.046 mol), and the reaction was allowed to run at roomtemperature for 8 hours. The pH of the reaction mixture was adjusted to8 by adding 1 mol/L hydrochloric acid, and the ethanol was evaporated,followed by addition of water (10 mL). The mixture was extracted with 20mL ethyl acetate three times, and the organic phases were combined,washed with saturated brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated to give 9.3 g of intermediate2-1, which was directly used in the next reaction without purification.

Step (2): Preparation of Ethyl 5-phenyl-1H-pyrazole-3-carboxylate(Intermediate 3-1)

The above obtained intermediate 2-1 (9.3 g, 0.042 mol) was added into around-bottom flask charged with 50 mL of ethanol, followed by additionof hydrazine hydrate (2.1 g, 0.042 mol) dropwise under stirring at roomtemperature. After the completion of the addition, the mixture wasrefluxed for 3 hours and then cooled to room temperature. The ethanolwas evaporated, and 10 mL of water was added. The mixture was extractedwith ethyl acetate (3×20 mL), and the organic phases were combined,washed with saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was recrystallized withethyl acetate/petroleum ether (1:5) to give 8.68 g of intermediate 3-1with a yield of 95.6%.

Step (3): Preparation of Ethyl4-chloro-5-phenyl-1H-pyrazole-3-carboxylate (Intermediate 4-1)

Intermediate 3-1 (2 g, 9.20 mmol) was added into a 100 mL round bottomflask, followed by addition of 12 mL of a mixed solvent of CH₃CN and DMF(CH₃CN:DMF=5:1). NCS was added to the above solution under stirring atroom temperature, and the resulting mixture was warmed to 60° C. Thereaction was allowed to run at 60° C. for 10 hours until the reactionwas complete. The acetonitrile was evaporated under reduced pressure,and the mixture was extracted with ethyl acetate (3×20 mL). The organicphases were combined, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a crude product of the intermediate 4, which wasseparated by column chromatography (ethyl acetate:petroleum ether=1:4)to give a pure product of intermediate 4-1 (1.16 g, 50.5%).

Step (4): Preparation of 4-chloro-5-phenyl-1H-pyrazole-3-methanol(Intermediate 5-1)

Intermediate 4-1 (1.16 g, 4.64 mmol) was added into a 100 mLround-bottom flask, followed by addition of 10 mL of anhydrous THF.LiAlH₄ (0.277 g, 6.96 mmol) was added in batches to the above solutionunder an ice bath and the protection of nitrogen atmosphere. Theresulting mixture was stirred at room temperature for 2 hours until thereaction was complete. Subsequently, saturated aqueous ammonium chloridesolution was added dropwise to the reaction solution under ice bath toquench the reaction. The mixture was filtered by suction, and thefiltrate was extracted with ethyl acetate. The organic phases werecombined, washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized with ethyl acetate/petroleum ether (1:3) to give a pureproduct of intermediate 5-1 (0.768 g, yield 79.6%).

Step (5): Preparation of 3-bromomethyl-4-chloro-5-phenyl-1H-pyrazole(Intermediate 6-1)

The above obtained intermediate 5-1 (0.768 g, 3.69 mmol) was added intoa 50 mL round-bottom flask, followed by addition of 15 mL ofacetonitrile. PBr₃ (1.20 g, 4.43 mmol) was added dropwise to the abovesolution under an ice bath. After completion of the addition, thereaction solution was warmed to 80° C. and the reaction was allowed torun for 1 hour. After the completion of the reaction, the reactionsolution was poured into ice water, and the acetonitrile was evaporatedunder reduced pressure. The pH was adjusted to weakly alkaline withsaturated NaHCO₃, and the mixture was filtered by suction. The filtratewas extracted with ethyl acetate, and the organic phases were combined,washed with saturated brine and dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was recrystallized withethyl acetate/petroleum ether (1:3) to give a pure product ofintermediate 6-1 (0.681 g, yield 89.6%).

Step (6): Preparation of the Target Compound I-1

6-(Cyclohexylmethyl)-5-ethyl-2-mercaptopyrimidin-4 (3H)-one 7-1 (0.003mol, 0.728 g) was added into 9 mL of DMF and stirred until dissolved,followed by addition of anhydrous K₂CO₃ (0.004 mol, 0.553 g). Theresulting mixture was stirred at room temperature for 30 minutes, andthen 5 mL of a solution of intermediate 6-1 (0.681 g, 0.003 mol) in DMFwas added. The reaction solution was stirred for 3 hours until thereaction was completed, and then poured into 10 mL of ice water, duringwhich a white solid precipitated out. The mixture was filtered orextracted with ethyl acetate to obtain a crude product, which waspurified by column chromatography with ethyl acetate/petroleum ether(1:4) as the eluent to give the target product I-1.

The product was obtained as a white crystal with a yield of 86%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.94-0.97 (t, 3H, J=7.2 Hz, CH₃), 0.99 (m, 2H,Cyclohexyl-H), 1.06-1.08 (m, 3H, Cyclohexyl-H), 1.56-1.59 (m, 5H,Cyclohexyl-H), 1.81 (m, 1H, Cyclohexyl-H), 2.32-2.34 (d, 2H, J=6.0 Hz,CH₂-Cyclohexyl), 2.36-2.38 (m, 2H, CH₂CH₃), 4.44 (s, 2H, CH₂—S),7.40-7.51 (m, 3H, Ph-H), 7.77-7.79 (m, 2H, Ph-H), 10.88 (br, 1H, NH),13.19 (br, 1H, NH); ¹³C NMR (DMSO d₆, 75 MHz) δ 13.19, 18.01, 25.00(2C), 25.73 (2C), 25.87, 32.63, 36.53, 40.76, 105.07, 121.05, 126.42,126.42, 126.42, 128.67 (3C), 140.28, 141.02, 155.86, 161.05, 162.92.

Compound I-2 was prepared according to method for preparing the targetcompound I-1 except that the step (3) was omitted.

The product was obtained as a white solid with a yield of 87%. ¹H NMR(CDCl₃, 300 MHz) δ 0.85-0.88 (t, 3H, J=8.1 Hz, CH₃), 0.97-1.00 (m, 2H,Cyclohexyl-H), 1.07-1.12 (m, 3H, Cyclohexyl-H), 1.65-1.69 (m, 5H,Cyclohexyl-H), 1.82 (m, 1H, Cyclohexyl-H), 2.46-2.48 (d, 2H, J=6.9 Hz,CH₂—Cyclohexyl), 2.51-2.53 (m, 2H, CH₂CH₃), 4.42 (s, 2H, CH₂—S), 6.52(s, 1H, pyrazole), 7.34-7.36 (m, 3H, Ph-H), 7.67-7.69 (m, 2H, Ph-H),10.24-10.73 (br, 1H, NH), 13.19 (br, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ13.37, 18.75, 26.31 (2C), 26.40, 26.90 (2C), 33.36, 37.50, 41.80,102.28, 122.74, 125.71 (2C), 128.32, 128.86 (2C), 130.56, 146.29,146.99, 156.37, 163.11, 164.73.

Compound I-3 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-bromophenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 74%. ¹H NMR(CDCl₃, 300 MHz) δ 0.89-0.91 (t, 3H, J=6.0 Hz, CH₃), 1.04 (m, 2H,Cyclohexyl-H), 1.13 (m, 3H, Cyclohexyl-H), 1.69 (m, 5H, Cyclohexyl-H),1.84 (m, 1H, Cyclohexyl-H), 2.53 (m, 2H, CH₂-Cyclohexyl), 2.53 (m, 2H,CH₂), 4.45 (s, 2H, CH₂S), 6.53 (s, 1H, pyrazole-H), 7.23-7.25 (m, 1H,Ph-H), 7.41-7.44 (m, 1H, Ph-H), 7.63-7.65 (m, 1H, Ph-H), 7.90 (m, 1H,Ph-H), 12.36 (br, 1H, NH), 13.19 (br, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ13.38, 18.75, 26.32 (5C), 33.38, 37.58, 41.90, 102.64, 122.64, 122.92,124.29, 128.73, 130.29, 131.00, 133.49, 144.90, 147.13, 156.42, 163.40,164.88.

Compound I-4 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-bromophenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 89%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.93-0.95 (t, 3H, J=7.2 Hz, CH₃), 0.98 (m, 2H,Cyclohexyl-H), 1.02-1.04 (m, 3H, Cyclohexyl-H), 1.52-1.55 (m, 5H,Cyclohexyl-H), 1.71 (m, 1H, Cyclohexyl-H), 2.33-2.35 (m, 2H,CH₂—Cyclohexyl), 2.33-2.35 (m, 2H, CH₂), 4.43 (s, 2H, CH₂—S), 7.42-7.45(m, 1H, Ph-H), 7.55-7.58 (m, 1H, Ph-H), 7.80-7.82 (m, 1H, Ph-H), 7.95(m, 1H, Ph-H), 13.01 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.58,18.26, 23.13, 25.77 (4C), 32.73, 36.87, 40.65, 104.93, 119.02, 121.85,125.25, 128.74, 130.77 (2C), 132.99, 140.95, 141.24, 160.40, 161.32,168.14.

Compound I-5 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-chlorophenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 85%. ¹H NMR(CDCl₃, 300 MHz) δ 0.97-1.01 (m, 2H, Cyclohexyl-H), 1.01-1.12 (t, 3H,J=7.2 Hz, CH₃), 1.17-1.21 (m, 3H, Cyclohexyl-H), 1.65-1.69 (m, 5H,Cyclohexyl-H), 1.80 (m, 1H, Cyclohexyl-H), 2.47-2.49 (d, 2H, J=6.6 Hz,CH₂—Cyclohexyl), 2.51-2.54 (m, 2H, CH₂), 4.41 (s, 2H, CH₂—S), 6.50 (s,1H, pyrazole-H), 7.25-7.30 (m, 2H, Ph-H), 7.56 (m, 1H, Ph-H), 7.58-7.70(m, 1H, Ph-H), 12.56 (br, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ 13.36,18.74, 26.13 (5C), 33.37, 37.61, 41.92, 102.60, 122.69, 123.82, 125.86,128.12, 130.05, 133.19, 134.73, 144.98, 147.21, 156.52, 163.40, 164.88.

Compound I-6 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-chlorophenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 90%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.88 (m, 2H, Cyclohexyl-H), 0.93-0.98 (t, 3H, J=7.2Hz, CH₃), 1.03-1.05 (m, 3H, Cyclohexyl-H), 1.53-1.56 (m, 5H,Cyclohexyl-H), 1.72 (m, 1H, Cyclohexyl-H), 2.34-2.36 (m, 2H,CH₂—Cyclohexyl), 2.34-2.36 (m, 2H, CH₂), 4.43 (s, 2H, CH₂—S), 7.44-7.53(m, 2H, Ph-H), 7.76-7.81 (m, 2H, Ph-H), 12.50 (br, 2H, 2NH); ¹³CNMR(DMSO-d₆, 75 MHz) δ 13.26, 18.05, 23.37, 25.72 (2C), 25.86 (2C), 32.62,36.62, 40.65, 105.34, 120.48, 124.85, 125.89, 128.02, 130.52, 131.97,133.39, 140.52, 141.12, 157.09, 161.09, 164.33.

Compound I-7 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-chlorophenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 88%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.97-0.99 (t, 3H, J=7.2 Hz, CH₃), 1.09 (m, 2H,Cyclohexyl-H), 1.18 (m, 3H, Cyclohexyl-H), 1.57 (m, 5H, Cyclohexyl-H),1.75 (m, 1H, Cyclohexyl-H), 2.35-2.39 (m, 2H, CH₂—Cyclohexyl), 2.35-2.39(m, 2H, CH₂CH₃), 4.39 (s, 2H, CH₂—S), 6.58-6.61 (s, 1H, pyrazole-H),7.28-7.45 (m, 2H, Ph-H), 7.69-7.45 (m, 2H, Ph-H), 12.78 (br, 1H, NH);¹³C NMR (DMSO-d₆, 75 MHz) δ 13.21, 18.03, 25.73 (2C), 25.86 (3C), 32.65,36.58, 40.76, 101.71, 121.98, 124.93, 126.61, 127.66, 128.68, 131.86,132.08, 145.91, 156.29, 160.85, 163.02.

Compound I-8 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 89%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.90 (m, 2H, Cyclohexyl-H), 0.95-0.99 (t, 3H, J=7.5Hz, CH₃), 1.06-1.09 (m, 3H, Cyclohexyl-H), 1.56-1.60 (m, 5H,Cyclohexyl-H), 1.75 (m, 1H, Cyclohexyl-H), 2.36-2.38 (m, 2H,CH₂—Cyclohexyl), 2.36-2.38 (m, 2H, CH₂), 4.39 (s, 2H, CH₂—S), 6.57 (s,1H, pyrazole-H), 7.18-7.24 (m, 2H, Ph-H), 7.73-7.77 (m, 2H, Ph-H), 12.78(br, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.18, 18.02, 25.40, 25.40,25.72, 25.85 (2C), 32.65, 36.58, 40.71, 101.55, 115.39, 115.68, 121.07,126.90, 127.00, 127.99, 144.42, 145.63, 156.32, 160.62, 161.56, 163.26.

Compound I-9 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 71%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-0.98 (m, 2H, Cyclohexyl-H), 1.04-1.06 (t, 3H,J=7.8 Hz, CH₃), 1.13-1.15 (m, 3H, Cyclohexyl-H), 1.50-1.58 (m, 5H,Cyclohexyl-H), 1.75 (m, 1H, Cyclohexyl-H), 2.35-2.37 (m, 2H,CH₂—Cyclohexyl), 2.35-2.37 (m, 2H, CH₂), 4.43 (s, 2H, CH₂—S), 7.29-7.35(m, 2H, Ph-H), 7.79-7.84 (m, 2H, Ph-H), 12.96 (br, 2H, 2NH); ¹³C NMR(DMSO-d₆, 75 MHz) δ 13.17, 17.99, 23.69, 25.72 (2C), 25.86 (2C), 32.61,36.51, 40.75, 101.97, 115.53, 115.82, 121.11, 128.54, 128.65 (2C),140.42, 141.63, 155.92, 161.08, 161.96, 162.95.

Compound I-10 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methoxyphenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 50%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.95-1.00 (t, 3H, J=7.2 Hz, CH₃), 1.02-1.12 (m, 2H,Cyclohexyl-H), 1.16-1.20 (m, 3H, Cyclohexyl-H), 1.59-1.62 (m, 5H,Cyclohexyl-H), 1.78 (m, 1H, Cyclohexyl-H), 2.36-2.38 (m, 2H,CH₂—Cyclohexyl), 2.40 (m, 2H, CH₂), 3.76 (s, 3H, OCH₃), 4.37 (s, 2H,CH₂—S), 6.49 (s, 1H, pyrazole-H), 6.95-6.98 (m, 2H, Ph-H), 7.62-7.65 (m,2H, Ph-H), 12.07-13.10 (br, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.23,18.02, 25.74 (2C), 25.88 (3C), 32.66, 36.58, 40.71, 55.06, 100.85,114.11 (2C), 121.10, 123.45, 126.31 (2C), 142.23, 145.48, 156.39,158.90, 160.65, 163.03.

Compound I-11 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-chloro-4-methoxyphenyl)ethanone was usedas the raw material 1 in the step (1).

The product was obtained as a white crystal with a yield of 53%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.88 (m, 2H, Cyclohexyl-H), 0.93-0.98 (t, 3H, J=6.9Hz, CH₃), 1.04-1.07 (m, 3H, Cyclohexyl-H), 1.54-1.57 (m, 5H,Cyclohexyl-H), 1.74 (m, 1H, Cyclohexyl-H), 2.34-2.36 (m, 2H, CH₂—Cyclohexyl), 2.34-2.36 (m, 2H, CH₂), 3.89 (s, 3H, OCH₃), 4.42 (s, 2H,CH ₂—S), 7.24-7.27 (s, 1H, Ph-H), 7.72-7.81 (m, 2H, Ph-H), 12.52-13.21(br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.18, 17.99, 23.71, 25.72(2C), 25.86 (2C), 32.61, 36.52, 40.24, 56.15, 104.76, 112.91, 121.29,123.5, 126.41, 127.59, 127.81, 154.49, 141.36, 142.55, 155.96, 160.95,162.96.

Compound I-12 was prepared according to method for preparing the targetcompound I-1 except that 1-(3,4-dichlorophenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 51%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.94 (m, 2H, Cyclohexyl-H), 0.96-0.99 (t, 3H, J=7.2Hz, CH₃), 1.05-1.08 (m, 3H, Cyclohexyl-H), 1.55-1.58 (m, 5H,Cyclohexyl-H), 1.72 (m, 1H, Cyclohexyl-H), 2.35-2.37 (m, 2H, CH₂—Cyclohexyl), 2.35-2.37 (m, 2H, CH₂), 4.39 (s, 2H, CH ₂—S), 6.68 (s,1H, pyrazole-H), 7.59-7.62 (m, 1H, Ph-H), 7.68-7.72 (m, 1H, Ph-H),7.94-7.95 (m, 1H, Ph-H), 12.81 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz)δ 13.19, 18.02, 24.90, 25.72 (2C), 25.86 (2C), 32.63, 36.58, 40.82,102.26, 121.06, 124.96, 126.47 (2C), 129.78, 130.82, 131.53, 141.48,144.69, 156.09, 161.07, 162.99.

Compound I-13 was prepared according to method for preparing the targetcompound I-1 except that 1-(3,4-dichlorophenyl)ethanone was used as theraw material 1 in the step (1).

The product was obtained as a white crystal with a yield of 82%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.93-0.98 (t, 3H, J=7.2 Hz, CH₃), 1.04 (m, 2H,Cyclohexyl-H), 1.04 (m, 3H, Cyclohexyl-H), 1.53-1.55 (m, 5H,Cyclohexyl-H), 1.70 (m, 1H, Cyclohexyl-H), 2.33-2.36 (m, 2H, CH₂—Cyclohexyl), 2.33-2.36 (m, 2H, CH₂), 4.42 (s, 2H, CH ₂S), 7.46-7.55(m, 2H, Ph-H), 7.98-7.99 (m, 1H, Ph-H), 12.72-13.36 (br, 2H, 2NH);¹³CNMR (DMSO-d₆, 75 MHz) δ 13.17, 17.99, 23.17, 25.70 (2C), 25.84 (2C),32.59, 36.52, 40.76, 105.57, 121.09, 124.86, 126.07, 128.73, 130.91,131.49, 133.42, 140.68, 141.77, 155.74, 161.08, 162.96.

Compound I-14 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 74%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.97-1.00 (m, 2H, Cyclohexyl-H), 1.06-1.10 (t, 3H,J=7.2 Hz, CH₃), 1.13-1.16 (m, 3H, Cyclohexyl-H), 1.64-1.68 (m, 5H,Cyclohexyl-H), 1.80 (m, 1H, Cyclohexyl-H), 2.45-2.47 (m, 2H, CH₂—Cyclohexyl), 2.45-2.47 (m, 2H, CH₂), 4.39 (s, 2H, CH ₂—S), 6.49 (s,1H, pyrazole-H), 6.96 (m, 1H, Ph-H), 7.28-7.46 (m, 3H, Ph-H), 12.40 (br,2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.32, 18.72, 26.30 (5C), 33.37,37.56, 41.90, 102.63, 112.64, 114.98, 121.33, 122.75, 130.36, 133.35,145.29, 147.05, 156.25, 161.46, 163.32, 164.73.

Compound I-15 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 89%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.95 (m, 3H, CH₃), 1.04 (m, 2H, Cyclohexyl-H), 1.04(m, 3H, Cyclohexyl-H), 1.53 (m, 5H, Cyclohexyl-H), 1.72 (m, 1H,Cyclohexyl-H), 2.34 (m, 2H, CH ₂-Cyclohexyl), 2.34 (m, 2H, CH₂), 4.43(s, 2H, CH ₂—S), 7.22 (m, 1H, Ph-H), 7.55-7.65 (m, 3H, Ph-H),12.98-13.05 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.15, 17.99,23.55, 25.70 (2C), 25.84 (2C), 32.59, 36.52, 40.76, 105.46, 112.89,115.10, 121.10, 122.35 (2C), 130.77, 140.68, 141.54, 155.95, 161.11,162.13, 162.95.

Compound I-16 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-chlorophenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 90%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.88 (m, 2H, Cyclohexyl-H), 0.93-0.98 (t, 3H, J=7.2Hz, CH₃), 1.03-1.05 (m, 3H, Cyclohexyl-H), 1.53-1.56 (m, 5H,Cyclohexyl-H), 1.74 (m, 1H, Cyclohexyl-H), 2.34-2.36 (m, 2H, CH₂-Cyclohexyl), 2.34-2.36 (m, 2H, CH₂), 4.43 (s, 2H, CH ₂—S), 7.52-7.55(m, 2H, Ph-H), 7.79-7.81 (m, 2H, Ph-H), 13.01 (br, 2H, 2NH); ¹³C NMR(DMSO-d₆, 75 MHz) δ 13.18, 17.99, 23.53, 25.71 (2C), 25.85 (2C), 32.60,36.52, 40.75, 105.26, 121.09, 128.03 (3C), 128.76 (2C), 133.06, 140.46,141.02, 155.78, 161.11, 162.93.

Compound I-17 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-hydroxyphenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 54%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-1.00 (t, 3H, J=7.2 Hz, CH₃), 1.09-1.12 (m, 2H,Cyclohexyl-H), 1.09-1.12 (m, 3H, Cyclohexyl-H), 1.59-1.62 (m, 5H,Cyclohexyl-H), 1.79 (m, 1H, Cyclohexyl-H), 2.36-2.40 (m, 2H, CH₂—Cyclohexyl), 2.36-2.40 (m, 2H, CH₂), 4.36 (s, 2H, CH ₂—S), 6.42 (s,1H, pyrazole-H), 6.78-6.81 (m, 2H, Ph-H), 7.50-7.53 (m, 2H, Ph-H), 9.62(br, 1H, OH), 12.67 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.22,18.04, 25.75, 25.88 (2C), 26.07 (2C), 32.67, 36.59, 40.76, 100.49,115.48 (2C), 121.42, 126.40 (2C), 128.38, 145.64, 156.39, 157.25,157.25, 160.82, 162.98.

Compound I-18 was prepared according to method for preparing the targetcompound I-1 except that 1-(3,4-difluorophenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 89%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.94-0.99 (t, 3H, J=7.2 Hz, CH₃), 1.05-1.08 (m, 2H,Cyclohexyl-H), 1.05-1.08 (m, 3H, Cyclohexyl-H), 1.55-1.59 (m, 5H,Cyclohexyl-H), 1.72 (m, 1H, Cyclohexyl-H), 2.32-2.38 (m, 2H, CH₂—Cyclohexyl), 2.32-2.38 (m, 2H, CH₂), 4.38 (s, 2H, CH ₂—S), 6.64 (s,1H, pyrazole-H), 7.38-7.45 (m, 1H, Ph-H), 7.48-7.59 (m, 1H, Ph-H),7.71-7.78 (m, 1H, Ph-H), 11.81-12.97 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75MHz) δ 13.16, 18.01, 24.98, 25.70 (2C), 25.84 (2C), 32.62, 36.59, 40.71,102.03, 113.8, 117.78, 121.04, 121.63, 129.61, 143.99, 145.48, 149.06,149.47, 156.27, 160.66, 163.12.

Compound I-19 was prepared according to method for preparing the targetcompound I-1 except that 1-(3,4-difluorophenyl)ethanone was used as theraw material 1 in the step (1).

The product was obtained as a white crystal with a yield of 68%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.92-0.97 (t, 3H, J=7.2 Hz, CH₃), 1.02-1.04 (m, 2H,Cyclohexyl-H), 1.12-1.16 (m, 3H, Cyclohexyl-H), 1.52-1.55 (m, 5H,Cyclohexyl-H), 1.72 (m, 1H, Cyclohexyl-H), 2.33-2.35 (m, 2H, CH₂-Cyclohexyl), 2.33-2.35 (m, 2H, CH₂), 4.42 (s, 2H, CH ₂—S), 7.51-7.57(m, 1H, Ph-H), 7.64-7.73 (m, 1H, Ph-H), 7.73-7.80 (m, 1H, Ph-H), 13.00(br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.12, 17.98, 23.26, 25.70(2C), 25.83 (2C), 32.59, 36.52, 40.75, 105.29, 115.24, 117.78, 121.10,123.29 (2C), 140.50, 141.28, 149.31, 149.23, 155.79, 161.07, 162.95.

Compound I-20 was prepared according to method for preparing the targetcompound I-1 except that 1-(2,4-difluorophenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 75%. ¹H NMR(CDCl₃, 30 0 MHz) δ 1.07-1.10 (m, 2H, Cyclohexyl-H), 1.12-1.17 (t, 3H,J=6.9 Hz, CH₃), 1.22-1.26 (m, 3H, Cyclohexyl-H), 1.66-1.70 (m, 5H,Cyclohexyl-H), 1.82 (m, 1H, Cyclohexyl-H), 2.48-2.56 (m, 2H, CH₂-Cyclohexyl), 2.48-2.56 (m, 2H, CH₂), 4.44 (s, 2H, CH ₂—S), 6.64 (s,1H, pyrazole-H), 6.85-6.92 (m, 2H, Ph-H), 7.76-7.7 (m, 1H, Ph-H),12.09-12.42 (br, 2H, 2NH); ¹³C NMR (CDCl₃, 75 MHz) δ 13.33, 18.72, 26.29(3C), 26.38 (2C), 33.36, 37.54, 41.90, 104.66, 111.90, 115.45, 115.62,122.75, 129.12, 141.28, 145.26, 159.5, 162.76, 156.33, 163.22, 164.79.

Compound I-21 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methylphenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 80%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-1.00 (t, 3H, J=6.9 Hz, CH₃), 1.11 (m, 2H,Cyclohexyl-H), 1.11 (m, 3H, Cyclohexyl-H), 1.59 (m, 5H, Cyclohexyl-H),1.80 (m, 1H, Cyclohexyl-H), 2.28 (s, 3H, CH ₃-Ph), 2.37 (m, 2H,Cyclohexyl-H), 2.37 (m, 2H, CH₂), 4.39 (s, 2H, CH ₂—S), 6.53 (s, 1H,pyrazole-H), 7.17-7.19 (m, 2H, Ph-H), 7.58-7.61 (m, 2H, Ph-H), 12.77(br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.21, 18.05, 20.70, 25.77(3C), 25.88 (2C), 32.70, 36.59, 40.89, 101.20, 121.16, 124.86 (2C),128.09, 129.23 (2C), 137.01, 142.32, 145.67, 156.31, 160.94, 162.89.

Compound I-22 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methylphenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 63%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.97-0.99 (m, 2H, Cyclohexyl-H), 1.06-1.12 (t, 3H,J=7.8 Hz, CH₃), 1.17 (m, 3H, Cyclohexyl-H), 1.52-1.59 (m, 5H,Cyclohexyl-H), 1.79 (m, 1H, Cyclohexyl-H), 2.31 (s, 3H, CH ₃-Ph),2.35-2.37 (m, 2H, CH₂-Cyclohexyl), 2.35-2.37 (m, 2H, CH₂), 4.44 (s, 2H,CH ₂—S), 7.25-7.28 (m, 2H, Ph-H), 7.65-7.6 (m, 2H, Ph-H), 12.94 (br, 2H,2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.17, 18.00, 20.76, 24.04, 25.76(2C), 25.89 (2C), 32.66, 36.51, 40.76, 104.82, 121.10, 126.68 (3C),129.22 (2C), 137.95, 140.17, 141.01, 156.00, 161.02, 162.93.

Compound I-23 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-methylphenyl)ethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 74%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.92 (m, 2H, Cyclohexyl-H), 0.96-1.01 (t, 3H, J=6.9Hz, CH₃), 1.08-1.14 (m, 3H, Cyclohexyl-H), 1.53-1.60 (m, 5H,Cyclohexyl-H), 1.80 (m, 1H, Cyclohexyl-H), 2.30 (s, 3H, CH ₃-Ph),2.37-2.39 (m, 2H, CH₂-Cyclohexyl), 2.37-2.39 (m, 2H, CH₂), 4.41 (s, 2H,CH ₂—S), 6.55 (s, 1H, pyrazole-H), 7.06-7.09 (m, 1H, Ph-H), 7.23-7.28(m, 1H, Ph-H), 7.50-7.54 (m, 2H, Ph-H), 12.79 (br, 2H, 2NH); ¹³CNMR(DMSO-d₆, 75 MHz) δ 13.18, 18.07, 20.92, 25.78 (3C), 25.89 (2C), 32.70,36.62, 40.91, 101.48, 121.17, 122.11, 125.55, 128.31, 128.53, 130.87,137.77, 145.19, 145.93, 156.32, 160.94, 162.91.

Compound I-24 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-methylphenyl)ethanone was used as the rawmaterial 1 in the step (1).

The product was obtained as a white crystal with a yield of 66%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.89 (m, 2H, Cyclohexyl-H), 0.95-0.99 (t, 3H, J=7.2Hz, CH₃), 1.08 (m, 3H, Cyclohexyl-H), 1.56-1.59 (m, 5H, Cyclohexyl-H),1.79 (m, 1H, Cyclohexyl-H), 2.30 (s, 3H, CH ₃-Ph), 2.33-2.37 (m, 2H,CH₂—Cyclohexyl), 2.33-2.37 (m, 2H, CH₂), 4.45 (s, 2H, CH ₂—S), 7.17-7.19(m, 1H, Ph-H), 7.31-7.36 (m, 1H, Ph-H), 7.57-7.59 (m, 2H, Ph-H), 12.95(br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.16, 18.02, 20.97, 23.97,25.76 (2C), 25.90 (2C), 32.67, 36.52, 40.79, 105.08, 121.10, 123.60,126.98 (2C), 128.52, 129.03, 137.81, 141.98, 142.53, 156.03, 161.03,162.94.

Compound I-25 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methylthiophenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 53%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-1.00 (t, 3H, J=7.2 Hz, CH₃), 1.08-1.10 (m, 2H,Cyclohexyl-H), 1.15 (m, 3H, Cyclohexyl-H), 1.58 (m, 5H, Cyclohexyl-H),1.78 (m, 1H, Cyclohexyl-H), 2.37 (s, 3H, CH ₃S), 2.46-2.50 (m, 2H,CH₂—Cyclohexyl), 2.46-2.50 (m, 2H, CH₂), 4.40 (s, 2H, CH ₂—S), 6.55 (CH,pyrazole), 7.25-7.28 (m, 2H, Ph-H), 7.64-7.67 (m, 2H, Ph-H), 12.78 (br,2H, 2NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 13.22, 14.52, 18.05, 25.77 (3C),25.89 (2C), 32.69, 36.58, 40.88, 101.32, 121.15, 125.41 (2C), 125.99(2C), 127.65, 137.69, 145.61, 156.25, 160.98, 162.90.

Compound I-26 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-trifluoromethylphenyl)ethanone was used asthe raw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 68%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.75 (m, 2H, Cyclohexyl-H), 0.96-0.98 (t, 3H, J=6.6Hz, CH₃), 1.06 (m, 3H, Cyclohexyl-H), 1.54 (m, 5H, Cyclohexyl-H), 1.72(m, 1H, Cyclohexyl-H), 2.34-2.36 (m, 2H, Cyclohexyl-H), 2.34-2.36 (m,2H, CH₂), 4.42 (s, 2H, CH ₂—S), 6.72 (CH, pyrazole-H), 7.59-7.60 (m, 2H,Ph-H), 8.01-8.0 (m, 2H, Ph-H), 12.58 (br, 2H, 2NH); ¹³C NMR (DMSO-d₆, 75MHz) δ 13.12, 18.00, 24.94, 25.68 (2C), 25.79 (2C), 32.61, 36.56, 40.70,102.09, 121.10, 122.28, 123.83, 125.88, 128.74, 129.56, 130.24, 132.89,144.05, 146.06, 156.22, 160.68, 163.11

Compound I-27 was prepared according to method for preparing the targetcompound I-1 except that 1-(3-trifluoromethylphenyl)ethanone was used asthe raw material 1 in the step (1).

The product was obtained as a white crystal with a yield of 63%. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.68-1.81 (m, 2H, Cyclohexyl-H), 1.85-1.90 (t, 3H,J=6.9 Hz, CH₃), 1.93 (m, 3H, Cyclohexyl-H), 2.06-2.45 (m, 5H,Cyclohexyl-H), 2.62 (m, 1H, Cyclohexyl-H), 3.25-3.27 (m, 2H,Cyclohexyl-H), 3.25-3.27 (m, 2H, CH ₂CH₃), 5.37 (s, 2H, CH ₂—S),8.52-8.64 (m, 2H, Ph-H), 8.93-9.04 (m, 2H, Ph-H), 13.94 (br, 2H, 2NH);¹³C NMR (DMSO-d₆, 75 MHz) δ 13.10, 17.98, 23.36, 25.66 (2C), 25.79 (2C),32.58, 36.51, 40.76, 105.54, 121.09 (2C), 122.58, 123.95, 124.66,128.96, 129.33, 129.92, 140.58, 141.26, 155.81, 161.05, 162.56.

Compound I-28 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-isopropylphenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 71%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.92 (m, 2H, Cyclohexyl-H), 0.96-1.01 (t, 3H, J=7.5Hz, CH₃), 1.08-1.10 (d, 6H, J=7.5 Hz, 2CH₃), 1.15-1.17 (m, 3H,Cyclohexyl-H), 1.59 (m, 5H, Cyclohexyl-H), 1.80 (m, 1H, Cyclohexyl-H),2.37-2.39 (m, 2H, CH₂-Cyclohexyl), 2.37-2.39 (m, 2H, CH₂), 2.81-2.85 (m,1H, CHMe₂), 4.41 (s, 2H, CH ₂—S), 6.53 (CH, pyrazole-H), 7.21-7.24 (m,2H, Ph-H), 7.60-7.63 (m, 2H, Ph-H), 12.78 (br, 1H, NH); ¹³C NMR(DMSO-d₆, 75 MHz) δ 13.19, 18.06, 23.62 (2), 25.77 (3), 25.89, 25.89,32.71, 33.16, 36.59, 40.92, 101.29, 121.15, 125.00 (2C), 126.53 (2C),126.53, 128.49, 145.66, 147.92, 156.35, 160.92, 162.90.

Compound I-29 was prepared according to method for preparing the targetcompound I-1 except that 1-(2,4-dimethylphenyl)ethanone was used as theraw material 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 65%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-1.00 (m, 2H, Cyclohexyl-H), 1.04-1.09 (t, 3H,J=7.2 Hz, CH₃), 1.17-1.25 (m, 3H, Cyclohexyl-H), 1.65 (m, 5H,Cyclohexyl-H), 1.84 (m, 1H, Cyclohexyl-H), 2.31 (s, 3H, CH ₃-Ph), 2.35(s, 3H, CH ₃-Ph), 2.44-2.50 (m, 2H, CH ₂-Cyclohexyl), 2.44-2.50 (m, 2H,CH₂), 4.46 (s, 2H, CH ₂—S), 6.35 (CH, pyrazole-H), 6.97-7.03 (m, 2H,Ph-H), 7.30-7.32 (m, 2H, Ph-H), 12.54 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 75MHz) δ 13.40, 18.77, 20.86, 21.23, 26.37, 26.50 (2C), 27.51 (2C), 33.43,37.43, 41.86, 105.16, 122.78, 126.82, 127.29, 129.03, 131.70, 135.80,138.29, 145.35, 146.58, 156.26, 163.03, 164.67.

Compound I-30 was prepared according to method for preparing the targetcompound I-1 except that 3,3-dimethylbutan-2-one was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 45%. ¹H NMR(CDCl₃, 300 MHz) δ 0.85 (m, 2H, Cyclohexyl-H), 1.02 (s, 9H, 3×CH₃),1.07-1.12 (t, 3H, J=7.5 Hz, CH₃), 1.34 (m, 1H, Cyclohexyl-H), 1.67-1.71(m, 7H, Cyclohexyl-H), 1.84 (m, 1H, Cyclohexyl-H), 2.44-2.47 (d, 2H,J=6.9 Hz, CH₂-Cyclohexyl), 2.51-2.56 (m, 2H, CH₂), 4.38 (s, 2H, CH ₂—S),6.05 (CH, pyrazole-H); ¹³C NMR (CDCl₃, 75 MHz) δ 13.32, 18.70, 26.34(2C), 26.44, 28.01 (2C), 30.26 (3C), 31.23, 33.35, 37.35, 41.76, 100.91,122.76, 142.18, 146.33, 155.36, 156.21, 162.80, 164.32.

Compound I-31 was prepared according to method for preparing the targetcompound I-1 except that acetaldehyde was used as the raw material 1 inthe step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 51%. ¹H NMR(CDCl₃, 300 MHz) δ 1.05 (m, 2H, Cyclohexyl-H), 1.07-1.12 (t, 3H, J=7.5Hz, CH₃), 1.17-1.26 (m, 3H, Cyclohexyl), 1.66-1.70 (m, 5H,Cyclohexyl-H), 1.80-1.85 (m, 1H, Cyclohexyl-H), 2.45-2.47 (d, 2H, J=7.2Hz, CH₂-Cyclohexyl), 2.51-2.53 (m, 2H, CH₂), 4.44 (s, 2H, CH ₂—S),6.27-6.28 (d, 1H, J=7.5 Hz, pyrazole-H), 7.52-7.53 (d, J=7.5 Hz, 1H,pyrazole-H); ¹³C NMR (CDCl₃, 75 MHz) δ 13.28, 18.71, 26.31 (2C), 26.41,27.19 (2C), 33.34, 37.36, 41.74, 104.76, 122.66, 131.71, 140.92, 145.81,156.11, 163.09, 164.65.

Compound I-32 was prepared according to method for preparing the targetcompound I-1 except that acetone was used as the raw material 1 in thestep (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 49%. ¹H NMR(CDCl₃, 300 MHz) δ 1.04 (m, 2H, Cyclohexyl-H), 1.07-1.12 (t, 3H, J=7.5Hz, CH₃), 1.16-1.23 (m, 3H, Cyclohexyl-H), 1.66-1.69 (m, 5H,Cyclohexyl-H), 1.80-1.85 (m, 1H, Cyclohexyl-H), 2.30 (s, 3H, CH₃-pyrazole), 2.44-2.46 (d, 2H, J=7.2 Hz, CH₂-Cyclohexyl), 2.50-2.53 (m,2H, CH₂ CH₃), 4.37 (s, 2H, CH ₂—S), 6.02 (CH, pyrazole-H), 11.01-11.45(br, 2H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ 11.48, 13.30, 18.68, 26.31,26.31 (2C), 27.33 (2C), 33.33, 37.33, 41.72, 104.13, 122.59, 141.94,146.81, 156.33, 163.02, 164.63.

Compound I-33 was prepared according to method for preparing the targetcompound I-1 except that 1-cyclopropylethanone was used as the rawmaterial 1 in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 38%. 1H NMR(CDCl₃, 300 MHz) δ 1.04 (m, 2H, Cyclohexyl-H), 1.07-1.12 (t, 3H, J=7.5Hz, CH₃), 1.17-1.20 (m, 4H, 2×CH₂), 1.23-1.26 (m, 3H, Cyclohexyl-H),1.66-1.69 (m, 5H, Cyclohexyl-H), 1.82 (m, 1H, Cyclohexyl-H), 1.87-1.94(m, 1H, cyclopropyl-H), 2.43-2.50 (d, 2H, J=7.5 Hz, CH₂-Cyclohexyl),2.53-2.55 (m, 2H, CH₂ CH₃), 4.36 (s, 2H, CH ₂—S), 5.88 (CH, pyrazole),11.72 (br, 2H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ 7.37, 7.87 (2C), 13.31,18.69, 26.32 (2C), 26.43, 27.26 (2C), 33.34, 37.36, 41.75, 100.94,122.59, 146.25, 149.44, 156.37, 163.01, 164.63.

Compound I-34 was prepared according to method for preparing the targetcompound I-1 except that 2-acetylpyridine was used as the raw material 1in the step (1) and the step (3) was omitted.

The product was obtained as a white crystal with a yield of 30%. ¹H NMR(CDCl₃, 300 MHz) δ 1.00-1.04 (m, 2H, Cyclohexyl-H), 1.07-1.12 (t, 3H,J=7.5 Hz, CH₃), 1.16-1.26 (m, 3H, Cyclohexyl-H), 1.63-1.69 (m, 5H,Cyclohexyl-H), 1.80-1.83 (m, 1H, Cyclohexyl-H), 2.45-2.47 (d, 2H, J=6.9Hz, CH₂-Cyclohexyl), 2.51-2.54 (m, 2H, CH₂ CH₃), 4.49 (s, 2H, CH ₂—S),6.75 (s, 1H, pyrazole-H), 7.20-7.21 (m, 1H, pyridine-H), 7.69 (m, 2H,pyridine-H), 8.63-8.64 (m, 1H, pyridine-H), 10.27-10.67 (br, 2H, 2NH);¹³C NMR (CDCl₃, 75 MHz) δ 13.32, 18.67, 26.28 (2C), 26.39, 27.08, 27.08,33.35, 37.38, 41.76, 101.19, 120.31, 122.69, 122.92, 137.01, 145.22,147.74, 148.91, 149.41, 156.10, 161.87, 164.82.

Compound I-35 was prepared according to method for preparing the targetcompound I-1 except that the step (3) was omitted and6-cyclohexylmethyl-5-isopropyl-thiopyrimidone was used as the reactant Ain the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 78%. ¹H NMR(CDCl₃, 300 MHz) δ 0.76-0.78 (m, 2H, Cyclohexyl-H), 0.97-1.00 (m, 2H,Cyclohexyl-H), 1.07-1.12 (m, 3H, Cyclohexyl-H), 1.26-1.29 (d, 6H, 2CH₃)1.65-1.69 (m, 3H, Cyclohexyl-H), 1.83 (m, 1H, Cyclohexyl-H), 2.41-2.43(d, 2H, J=7.0 Hz, CH ₂—Cyclohexyl), 2.86-3.23 (m, 1H, CHMe₂), 4.43 (s,2H, CH ₂—S), 6.51 (s, 1H, pyrazole-H), 7.32-7.34 (m, 3H, Ph-H),7.66-7.71 (m, 2H, Ph-H), 10.36 (br, 1H, NH), 13.19 (br, 1H, NH).

Compound I-36 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-chlorophenyl)-acetophenone was used as theraw material 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-isopropyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 80%. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.01-1.08 (m, 2H, Cyclohexyl-H), 1.18 (m, 3H,Cyclohexyl-H), 1.53 (m, 5H, Cyclohexyl-H), 1.76 (m, 1H, Cyclohexyl-H),2.35-2.39 (m, 2H, CH ₂-Cyclohexyl), 2.86-3.19 (m, 1H, CHMe₂), 4.35 (s,2H, CH ₂—S), 6.57-6.60 (s, 1H, pyrazole-H), 7.26-7.43 (m, 2H, Ph-H),7.67-7.73 (m, 2H, Ph-H), 12.77 (br, 1H, 2NH).

Compound I-37 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1) and 6-cyclohexylmethyl-5-isopropyl-thiouracilA was used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 82%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.98-1.01 (m, 2H, Cyclohexyl-H), 1.15-1.17 (m, 3H,Cyclohexyl-H), 1.26-1.29 (d, 6H, 2CH₃), 1.51-1.57 (m, 5H, Cyclohexyl-H),1.76 (m, 1H, Cyclohexyl-H), 2.33-2.36 (m, 2H, CH ₂—Cyclohexyl),2.86-3.24 (m, 1H, CHMe₂), 4.41 (s, 2H, CH ₂—S), 7.29-7.34 (m, 2H, Ph-H),7.79-7.82 (m, 2H, Ph-H), 12.96 (br, 2H, 2NH).

Compound I-38 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-hydroxyphenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-isopropyl-thiouracil A was used in the S-alkylationreaction of step (6).

The product was obtained as a white crystal with a yield of 64%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-1.10 (m, 5H, Cyclohexyl-H), 1.58-1.60 (m, 5H,Cyclohexyl-H), 1.79 (m, 1H, Cyclohexyl-H), 2.36-2.40 (m, 2H,CH₂—Cyclohexyl) 2.86-3.28 (m, 1H, CHMe₂), 4.42 (s, 2H, CH₂—S), 6.41 (s,1H, pyrazole-H), 6.77-6.80 (m, 2H, Ph-H), 7.51-7.54 (m, 2H, Ph-H), 9.22(br, 1H, OH), 12.13 (br, 2H, 2NH).

Compound I-39 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-isopropyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 87%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.88-0.92 (m, 2H, Cyclohexyl-H), 1.04-1.06 (m, 3H,Cyclohexyl-H), 1.26-1.29 (d, 6H, 2CH₃), 1.53-1.58 (m, 5H, Cyclohexyl-H),1.75 (m, 1H, Cyclohexyl-H), 2.26-2.28 (m, 2H, CH ₂—Cyclohexyl),2.86-3.26 (m, 1H, CHMe₂), 4.41 (s, 2H, CH ₂—S), 6.56 (s, 1H,pyrazole-H), 7.17-7.22 (m, 2H, Ph-H), 7.68-7.72 (m, 2H, Ph-H), 12.68(br, 1H, 2NH).

Compound I-40 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methoxyphenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-isopropyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 50%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.96-0.98 (m, 2H, Cyclohexyl-H), 1.16-1.21 (m, 3H,Cyclohexyl-H), 1.58-1.62 (m, 5H, Cyclohexyl-H), 1.81 (m, 1H,Cyclohexyl-H), 2.34-2.36 (m, 2H, CH ₂-Cyclohexyl), 2.84-3.26 (m, 1H,CHMe₂), 3.86 (s, 3H, OCH₃), 4.39 (s, 2H, CH ₂—S), 6.47 (s, 1H,pyrazole-H), 6.94-6.97 (m, 2H, Ph-H), 7.61-7.64 (m, 2H, Ph-H), 12.10(br, 1H, NH).

Compound I-41 was prepared according to method for preparing the targetcompound I-1 except that the step (3) was omitted and6-cyclohexylmethyl-5-methyl-thiouracil was used as the reactant A in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 85%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.94-1.00 (m, 2H, cyclohexyl-H), 1.08-1.11 (m, 3H,Cyclohexyl-H), 1.58-1.73 (m, 6H, Cyclohexyl-H), 1.87 (s, 3H, CH₃),2.39-2.41 (d, 2H, CH₂—Cyclohexyl), 4.38 (s, 2H, CH₂—S), 6.59 (s, 1H,pyrazole-H), 7.28-7.30 (m, 1H, Ph-H), 7.36-7.41 (t, 2H, J=7.23 Hz,Ph-H), 7.70-7.72 (d, 2H, Ph-H), 12.84 (br, 2H, 2NH).

Compound I-42 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-methyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 87%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.93-0.97 (m, 2H, Cyclohexyl-H), 1.07-1.10 (m, 3H,Cyclohexyl-H), 1.57-1.60 (m, 6H, Cyclohexyl-H), 1.88 (s, 3H, CH₃),2.38-2.41 (d, 2H, CH₂-Cyclohexyl), 4.38 (s, 2H, CH₂—S), 6.58 (s, 1H,pyrazole-H), 7.20-7.26 (m, 2H, J=8.8 Hz, Ph-H), 7.73-7.77 (m, 2H, Ph-H),12.77 (br, 1H, NH).

Compound I-43 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methoxyphenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-methyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 62%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.95-0.99 (m, 2H, Cyclohexyl-H), 1.11-1.13 (m, 3H,Cyclohexyl-H), 1.59-1.63 (m, 6H, Cyclohexyl-H), 1.88 (s, 3H, CH₃),2.39-2.42 (m, 2H, CH ₂-Cyclohexyl), 3.77 (s, 3H, OCH₃), 4.36 (s, 2H, CH₂—S), 6.49 (s, 1H, pyrazole-H), 6.95-6.98 (m, 2H, Ph-H), 7.62-7.65 (m,2H, Ph-H), 12.70 (br, 2H, 2NH).

Compound I-44 was prepared according to method for preparing the targetcompound I-1 except that the step (3) was omitted and6-cyclohexylmethylthiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 83%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.89-0.97 (m, 2H, Cyclohexyl-H), 1.09-1.17 (m, 3H,Cyclohexyl-H), 1.58-1.62 (m, 6H, Cyclohexyl-H), 2.32-2.34 (d, 2H, CH₂-Cyclohexyl), 4.40 (s, 2H, CH ₂—S), 5.96 (s, 1H, Pyrimidone-H), 6.61(s, 1H, pyrazole-H), 7.27-7.32 (t, 1H, J=7.30 Hz, Ph-H), 7.37-7.42 (t,2H, J=7.47 Hz, Ph-H), 7.70-7.72 (d, 2H, Ph-H), 12.80 (br, 2H, 2NH).

Compound I-45 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-fluorophenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethylthiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 89%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.88-0.92 (m, 2H, Cyclohexyl-H), 1.08-1.11 (m, 3H,Cyclohexyl-H), 1.57-1.61 (m, 6H, Cyclohexyl-H), 2.32-2.34 (d, 2H, CH₂-Cyclohexyl), 4.40 (s, 2H, CH ₂—S), 5.96 (s, 1H, Pyrimidone-H), 6.59(s, 1H, pyrazole-H), 7.20-7.26 (m, 2H, Ph-H), 7.73-7.78 (m, 2H, Ph-H),12.79 (br, 1H, NH).

Compound I-46 was prepared according to method for preparing the targetcompound I-1 except that 1-(4-methoxyphenyl)ethanone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethylthiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 47%. ¹H NMR(DMSO-d₆, 300 MHz) δ 0.90-0.97 (m, 2H, Cyclohexyl-H), 1.10-1.17 (m, 3H,Cyclohexyl), 1.59-1.72 (m, 6H, Cyclohexyl), 2.32-2.3 4 (d, 2H,CH₂-Cyclohexyl), 3.77 (s, 3H, OCH3), 4.38 (s, 2H, CH2-S), 5.96 (s, 1H,Pyrimidone-H), 6.50 (s, 1H, pyrazole-H), 6.95-6.98 (d, 2H, Ph-H),7.62-7.65 (m, 2H, Ph-H), 12.72 (br, 2H, NH).

Compound I-47 was prepared according to method for preparing the targetcompound I-1 except that 4′-hydroxy-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-5-methyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 65%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.94-1.02 (m, 2H, Cyclohexyl-H), 1.08-1.22 (m, 4H,Cyclohexyl-H), 1.56-1.63 (m, 5H, Cyclohexyl-H), 1.89 (s, 3H, CH₃),2.40-2.42 (d, 2H, J=6.88 Hz, CH ₂—Cyclohexyl), 4.35 (s, 2H, CH ₂—S),6.43 (s, 1H, pyrazole-H), 6.78-6.80 (d, 2H, J=8.52 Hz, Ph-H), 7.50-7.52(d, 2H, J=8.52 Hz, Ph-H), 9.61 (s, 1H, OH), 12.67 (br, 2H, NH); ¹³C NMR(DMSO-d₆, 100 MHz) δ 10.99, 26.19 (3C), 26.38 (2C), 33.11, 37.18, 42.02,101.03, 115.97 (2C), 122.27, 126.90 (2C), 131.69, 137.35, 145.92,156.77, 157.72, 162.04, 163.75.

Compound I-48 was prepared according to method for preparing the targetcompound I-1 except that 6-cyclohexylmethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 44%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.85-0.93 (m, 2H, Cyclohexyl-H), 1.01-1.18 (m, 3H,Cyclohexyl-H), 1.53-1.58 (m, 5H, Cyclohexyl-H), 1.67-1.71 (m, 1H,Cyclohexyl-H), 2.30-2.32 (d, 2H, J=7.00 Hz, CH ₂—Cyclohexyl), 4.46 (s,2H, CH ₂—S), 5.96 (s, 1H, Pyrimidone-H), 7.39-7.43 (t, 1H, J=7.32 Hz,Ph-H), 7.47-7.51 (t, 2H, J=7.44 Hz, Ph-H), 7.78-7.80 (d, 2H, J=7.56 Hz,Ph-H), 13.19 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 26.03 (3C),26.37 (2C), 32.89, 36.60, 44.70, 105.66, 107.62, 126.96 (2C), 128.96,129.22, 132.95, 138.53, 141.39, 152.49, 157.05, 162.06, 164.69.

Compound I-49 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-benzyl-5-ethyl-thiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 83%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.93-0.96 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.44-2.47(m, 2H, CH ₂—CH₃), 3.92 (s, 2H, CH ₂-Ph), 4.36 (s, 2H, CH ₂—S), 6.41 (s,1H, pyrazole-H), 7.17-7.30 (m, 7H, Ph-H), 7.69-7.73 (m, 2H, Ph-H), 12.80(br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.57, 18.71, 25.70, 40.15,102.15, 116.09 (2C), 121.68, 126.70, 127.50 (2C), 128.80 (2C), 129.33(2C), 133.41, 138.99, 141.63, 145.36, 148.50, 157.30, 160.94, 163.37.

Compound I-50 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 76%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.93-0.97 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.43-2.48(m, 2H, CH ₂—CH₃), 3.83 (s, 2H, CH ₂-Ph), 4.38 (s, 2H, CH ₂—S), 5.90 (s,2H, O—CH ₂—O), 6.45 (s, 1H, pyrazole-H), 6.74-6.80 (m, 2H, Ph-H), 6.87(s, 1H, Ph-H), 7.22-7.26 (t, 2H, J=8.8 Hz, Ph-H), 7.70-7.73 (m, 2H,Ph-H), 12.77 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.62, 18.63,25.43, 39.67, 101.16, 102.11, 108.57, 109.77, 116.07 (2C), 121.52,122.23, 127.47, 129.38, 132.63, 135.07, 140.08, 143.08, 146.07, 147.61,154.08, 157.17, 160.93, 163.36.

Compound I-51 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(2′,6′-dichlorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 62%. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.13 (t, 3H, J=7.0 Hz, CH₂—CH ₃), 2.56-2.58(m, 2H, CH ₂—CH₃), 3.98 (s, 2H, CH ₂-Ph), 4.26 (s, 2H, CH ₂—S), 6.00 (s,1H, pyrazole-H), 7.18-7.29 (m, 3H, Ph-H), 7.42-7.44 (d, 2H, J=7.96 Hz,Ph-H), 7.67-7.71 (m, 2H, Ph-H), 12.80 (br, 2H, NH); ¹³C NMR (DMSO-d₆,100 MHz) δ 13.06, 18.39, 35.24, 43.13, 101.62, 116.14 (2C), 127.48 (2C),128.48 (2C), 129.52, 135.05, 136.12 (2C), 139.48, 140.40, 142.88,149.36, 151.11, 157.83, 160.93, 163.36.

Compound I-52 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(3′,5′-difluorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 78%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.93-0.97 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.45-2.49(m, 2H, CH ₂—CH₃), 3.96 (s, 2H, CH ₂-Ph), 4.34 (s, 2H, CH ₂—S), 6.41 (s,1H, pyrazole-H), 7.01-7.06 (m, 3H, Ph-H), 7.21-7.26 (t, 2H, J=8.8 Hz,Ph-H), 7.67-7.71 (m, 2H, Ph-H), 12.80 (br, 2H, NH); ¹³C NMR (DMSO-d₆,100 MHz) δ 13.55, 18.60, 25.76, 39.42, 102.01, 102.39, 112.56 (2C),115.98 (2C), 121.97, 127.45 (2C), 139.46, 143.50, 149.37, 154.05,157.54, 159.39, 160.93, 161.46, 163.36, 163.90.

Compound I-53 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-benzyl-5-ethyl-thiouracil A was used inthe S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 72%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.89-0.92 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.41-2.47(m, 2H, CH ₂—CH₃), 3.90 (s, 2H, CH ₂-Ph), 4.43 (s, 2H, CH ₂—S),7.14-7.17 (m, 1H, Ph-H), 7.21-7.27 (m, 4H, Ph-H), 7.54-7.65 (m, 2H,Ph-H), 7.75-7.80 (m, 1H, Ph-H), 13.06 (br, 2H, NH); ¹³C NMR (DMSO-d₆,100 MHz), δ 13.46, 18.67, 24.01, 40.12, 105.95, 116.04, 118.56, 121.68,124.01, 126.64, 128.73 (2C), 129.20 (2C), 136.42, 138.98, 143.77,146.08, 148.68, 151.12, 156.83, 160.89, 163.76.

Compound I-54 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-cyclohexylmethyl-thiouracil A was usedin the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 67%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.84-0.92 (m, 2H, Cyclohexyl-H), 1.06-1.19 (m, 3H,Cyclohexyl-H), 1.54-1.66 (m, 6H, Cyclohexyl-H), 2.30-2.32 (d, 2H, J=6.9Hz, CH ₂-Cyclohexyl), 4.45 (s, 2H, CH ₂—S), 5.97 (s, 1H, Pyrimidone-H),7.55-7.61 (m, 1H, Ph-H), 7.66-7.68 (m, 1H, Ph-H), 7.76-7.82 (m, 1H,Ph-H), 13.48 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 26.00 (3C),26.35 (2C), 32.86, 36.61, 44.73, 105.89, 107.67, 115.87, 118.55, 123.96,131.36, 136.14, 140.00, 148.68, 151.12, 155.79, 161.40, 164.00.

Compound I-55 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1) and6-(2′,6′-dichlorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 79%. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.13 (m, 3H, CH₂—CH ₃), 2.56-2.57 (m, 2H, CH₂—CH₃), 3.96 (s, 2H, CH ₂-Ph), 4.23 (s, 2H, CH ₂—S), 7.22-7.26 (m, 1H,Ph-H), 7.39-7.42 (m, 2H, Ph-H), 7.58-7.62 (m, 2H, Ph-H), 7.74-7.79 (m,1H, Ph-H), 13.12 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.06,18.36, 24.59, 35.16, 105.76, 115.97, 118.70, 124.04, 128.37 (2C),129.39, 131.39, 134.95, 136.04 (2C), 138.15, 144.28, 148.76, 149.88,151.08, 155.79, 159.86, 163.23.

Compound I-56 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-cyclohexylmethyl-5-methyl-thiouracil Awas used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 54%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.94 (m, 2H, Cyclohexyl-H), 1.05-1.07 (m, 3H,Cyclohexyl-H), 1.54-1.67 (m, 6H, Cyclohexyl-H), 1.87 (s, 3H, CH₃),2.37-2.39 (d, 2H, J=6.9 Hz, CH ₂—Cyclohexyl), 4.43 (s, 2H, CH ₂—S),7.56-7.61 (m, 1H, Ph-H), 7.67-7.69 (m, 1H, Ph-H), 7.78-7.83 (m, 1H,Ph-H), 13.28 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz), δ 10.94, 26.14(3C), 26.35 (2C), 33.01, 37.16, 41.87, 105.78, 115.86, 118.53, 123.93,130.67, 137.17, 141.50, 145.16, 148.66, 151.04, 155.40, 161.08, 163.99.

Compound I-57 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1) and6-(3′,5′-difluorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 62%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.89-0.93 (t, 3H, J=7.4 Hz, CH₂—CH ₃), 2.40-2.46(m, 2H, CH ₂—CH₃), 3.95 (s, 2H, CH ₂-Ph), 4.39 (s, 2H, CH ₂—S),6.95-7.03 (m, 3H, Ph-H), 7.53-7.65 (t, 2H, Ph-H), 7.74-7.78 (m, 1H,Ph-H), 13.31 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz), δ 13.49, 18.58,23.69, 39.98, 102.18, 105.82, 112.37 (2C), 115.88, 118.51, 123.93,128.26, 132.09, 135.06, 137.44, 143.50 (2C), 146.51, 148.59, 151.04,157.69, 161.41, 163.86.

Compound I-58 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-benzyl-5-ethyl-thiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 76%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.96 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.43-2.47(m, 2H, CH ₂—CH₃), 3.92 (s, 2H, CH ₂-Ph), 4.37 (s, 2H, CH ₂—S), 6.49 (s,1H, pyrazole-H), 7.16-7.19 (m, 1H, Ph-H), 7.23-7.29 (m, 4H, Ph-H),7.44-7.54 (m, 2H, Ph-H), 7.70-7.75 (m, 1H, Ph-H), 12.83 (br, 2H, NH);¹³C NMR (DMSO-d₆, 100 MHz) δ 13.55, 18.70, 24.32, 40.14, 102.62, 114.35,118.36, 122.23, 126.69, 128.78 (2C), 129.33 (2C), 131.66, 139.01,142.37, 148.10, 148.91, 150.48, 151.34, 156.80, 160.86, 163.55.

Compound I-59 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-cyclohexylmethyl-thiouracil A was used in the S-alkylation reaction ofthe step (6).

The product was obtained as a white crystal with a yield of 82%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.83-0.94 (m, 2H, Cyclohexyl-H), 1.05-1.18 (m, 3H,Cyclohexyl-H), 1.54-1.67 (m, 6H, Cyclohexyl-H), 2.31-2.33 (d, 2H, J=6.9Hz, CH ₂-Cyclohexyl), 4.40 (s, 2H, CH ₂—S), 5.96 (s, 1H, Pyrimidone-H),6.67 (s, 1H, pyrazole-H), 7.42-7.49 (m, 1H, Ph-H), 7.57-7.60 (m, 1H,Ph-H), 7.74-7.79 (m, 1H, Ph-H), 12.80 (br, 2H, NH); ¹³C NMR (DMSO-d₆,100 MHz), δ 26.02 (3C), 26.35 (2C), 32.90, 36.65, 44.87, 102.69, 107.73,114.35, 118.34, 112.17, 130.37, 136.04, 139.42, 148.51, 150.95, 155.06,164.34, 167.35.

Compound I-60 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(2′,6′-dichlorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 73%. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.13 (t, 3H, J=7.1 Hz, CH₂—CH ₃), 2.54-2.59(m, 2H, CH ₂—CH₃), 3.99 (s, 2H, CH ₂-Ph), 4.24-4.26 (m, 2H, CH ₂—S),6.08 (s, 1H, pyrazole-H), 7.20-7.24 (m, 1H, Ph-H), 7.40-7.43 (m, 2H,Ph-H), 7.49-7.50 (m, 2H, Ph-H), 7.66-7.71 (m, 1H, Ph-H), 12.81 (br, 2H,NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.04, 18.38, 24.43, 35.22, 102.11,114.28, 118.41, 122.25, 128.46 (2C), 129.52, 135.03, 136.10 (2C),141.49, 144.77, 148.11, 148.91, 150.58, 151.34, 157.94, 160.84, 163.30.

Compound I-61 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(3′,5′-difluorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 82%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.96 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.48(m, 2H, CH ₂—CH₃), 3.96 (s, 2H, CH ₂-Ph), 4.35 (s, 2H, CH ₂—S), 6.49 (s,1H, pyrazole-H), 6.99-7.03 (m, 3H, Ph-H), 7.42-7.49 (m, 1H, Ph-H),7.52-7.55 (m, 1H, Ph-H), 7.69-7.74 (m, 1H, Ph-H), 12.86 (br, 2H, NH);¹³C NMR (DMSO-d₆, 100 MHz) δ 13.51, 18.59, 25.23, 39.44, 102.24, 102.51,112.53 (2C), 114.33, 118.29, 122.15, 130.72, 134.39, 137.46, 140.05,143.51, 145.42, 148.49, 150.93, 159.52, 161.44, 163.88 (2C).

Compound I-62 was prepared according to method for preparing the targetcompound I-1 except that 3′,4′-difluoro-acetophenone was used as the rawmaterial 1 in the step (1), the step (3) was omitted and6-(1′,3′-benzodioxy)-5-ethyl-thiouracil A was used in the S-alkylationreaction of the step (6).

The product was obtained as a white crystal with a yield of 85%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.96 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.47(m, 2H, CH ₂—CH₃), 3.83 (s, 2H, CH ₂-Ph), 4.38 (s, 2H, CH ₂—S), 5.89 (s,2H, O—CH ₂—O), 6.53 (s, 1H, pyrazole-H), 6.73-6.79 (m, 2H, Ph-H), 6.85(s, 1H, Ph-H), 7.43-7.53 (m, 2H, Ph-H), 7.71-7.76 (m, 1H, Ph-H), 12.81(br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.59, 18.62, 25.54, 39.66,101.15, 102.60, 108.54, 109.75, 114.36, 118.32, 122.22 (2C), 132.63,136.00, 138.70, 142.21, 146.05, 147.60, 148.13, 148.91, 150.47, 151.34,161.01, 163.70.

Compound I-63 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and6-(3′,5′-difluorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 77%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.91-0.94 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.47(m, 2H, CH ₂—CH₃), 3.95 (s, 2H, CH ₂-Ph), 4.39 (s, 2H, CH ₂—S),6.97-7.04 (m, 3H, Ph-H), 7.31-7.36 (t, 2H, J=8.6 Hz, Ph-H), 7.78-7.82(m, 2H, Ph-H), 12.98 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.50,18.58, 24.50, 39.40, 102.20, 105.50, 112.44 (2C), 116.21 (2C), 122.14,129.17 (2C), 138.96, 143.46, 149.22, 152.52, 156.05, 159.35, 161.26,161.43, 163.71, 163.87.

Compound I-64 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and6-(2′,6′-difluorobenzyl)-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 72%. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.08-1.12 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.54-2.59(m, 2H, CH ₂—CH₃), 3.95 (s, 2H, CH ₂-Ph), 4.22 (s, 2H, CH ₂—S),7.22-7.26 (t, 1H, J=8.2 Hz, Ph-H), 7.33-7.45 (m, 4H, Ph-H), 7.77-7.81(m, 2H, Ph-H), 12.91 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.06,18.37, 24.31, 35.56, 105.40, 116.31 (2C), 128.37 (2C), 129.23 (2C),129.38, 134.98, 136.06 (2C), 138.83, 139.55, 142.29, 148.66, 151.76,158.26, 161.31, 163.75.

Compound I-65 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-(1′,3′-benzodioxy)-5-ethyl-thiouracil Awas used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 83%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.90-0.94 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.41-2.46(m, 2H, CH ₂—CH₃), 3.81 (s, 2H, CH ₂-Ph), 4.44 (s, 2H, CH ₂—S), 5.92 (s,2H, O—CH ₂—O), 6.73-6.80 (m, 2H, Ph-H), 6.83 (s, 1H, Ph-H), 7.32-7.36(m, 2H, Ph-H), 7.80-7.84 (m, 2H, Ph-H), 13.06 (br, 2H, NH); ¹³C NMR(DMSO-d₆, 100 MHz) δ 13.53, 18.62, 24.09, 39.66, 101.16, 105.59, 108.48,109.61, 116.22 (2C), 121.38, 122.15, 126.59, 129.21 (2C), 132.60,139.72, 142.56, 146.06, 147.59, 153.95, 157.36, 161.27, 163.71.

Compound I-66 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-benzyl-5-ethyl-thiouracil A was used inthe S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 79%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.90-0.93 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.48(m, 2H, CH ₂—CH₃), 3.90 (s, 2H, CH ₂-Ph), 4.43 (s, 2H, CH ₂—S),7.14-7.17 (t, 1H, J=7.0 Hz, Ph-H), 7.22-7.25 (t, 2H, J=7.6 Hz, Ph-H),7.27-7.29 (d, 2H, J=7.2 Hz, Ph-H), 7.32-7.36 (t, 2H, J=8.7 Hz, Ph-H),7.81-7.84 (m, 2H, Ph-H), 12.97 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)δ 13.48, 18.69, 24.30, 40.17, 105.60, 116.25 (2C), 121.49, 126.64,128.73 (2C), 129.25 (4C), 133.92, 138.97, 140.12, 144.11, 148.84,156.97, 161.28, 163.72.

Compound I-67 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-cyclohexylmethyl-thiouracil A was usedin the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 68%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.84-0.92 (m, 2H, Cyclohexyl-H), 1.03-1.11 (m, 3H,Cyclohexyl-H), 1.55-1.69 (m, 6H, Cyclohexyl-H), 2.30-2.32 (d, 2H, J=7.0Hz, CH ₂-Cyclohexyl), 4.45 (s, 2H, CH ₂—S), 5.96 (s, 1H, Pyrimidone-H),7.32-7.36 (t, 2H, J=8.8 Hz, Ph-H), 7.81-7.84 (m, 2H, Ph-H), 13.09 (br,2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 26.02 (3C), 26.35, 32.87, 36.59,44.71, 105.56, 107.69, 116.21 (2C), 126.33, 129.15 (2C), 138.01, 142.77,148.11, 158.68, 161.25, 163.70, 167.53.

Compound I-68 was prepared according to method for preparing the targetcompound I-1 except that 4′-fluoro-acetophenone was used as the rawmaterial 1 in the step (1) and 6-cyclohexylmethyl-5-methyl-thiouracil Awas used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 86%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.97 (m, 2H, Cyclohexyl-H), 1.06-1.07 (m, 3H,Cyclohexyl-H), 1.51-1.58 (m, 5H, Cyclohexyl-H), 1.70 (s, 1H,Cyclohexyl-H), 1.87 (s, 3H, CH₃), 2.37-2.39 (d, 2H, J=6.9 Hz, CH₂—Cyclohexyl), 4.43 (s, 2H, CH ₂—S), 7.32-7.36 (t, 2H, J=8.7 Hz, Ph-H),7.80-7.84 (m, 2H, Ph-H), 12.87 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)δ 24.13, 26.16 (3C), 26.36 (2C), 33.04, 37.12, 41.87, 105.50, 116.20(2C), 129.13 (2C), 139.22, 146.53, 152.02, 156.28, 159.55, 161.24,162.22, 163.69.

Compound I-69 was prepared according to method for preparing the targetcompound I-1 except that 6-(3′,5′-difluorobenzyl)-5-ethyl-thiouracil Awas used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 82%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.92-0.95 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.48(m, 2H, CH ₂—CH₃), 3.95 (s, 2H, CH ₂-Ph), 4.40 (s, 2H, CH ₂—S),6.99-7.04 (m, 3H, Ph-H), 7.39-7.43 (t, 1H, J=7.2 Hz, Ph-H), 7.47-7.51(t, 2H, J=7.4 Hz, Ph-H), 7.75-7.77 (d, 2H, J=7.5 Hz, Ph-H), 12.94 (br,2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.53, 18.58, 24.45, 39.41,102.21, 105.61, 112.48 (2C), 122.13, 126.90 (2C), 129.02, 129.23 (2C),133.45, 138.70, 143.46, 149.82, 154.63, 156.71, 159.40, 161.44, 163.68.

Compound I-70 was prepared according to method for preparing the targetcompound I-1 except that 6-(2′,6′-dichlorobenzyl)-5-ethyl-thiouracil Awas used in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 75%. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.12 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.54-2.59(m, 2H, CH ₂—CH₃), 3.96 (s, 2H, CH ₂-Ph), 4.22 (s, 2H, CH ₂—S),7.22-7.26 (t, 1H, J=8.0 Hz, Ph-H), 7.40-7.43 (m, 3H, Ph-H), 7.48-7.52(t, 2H, J=7.5 Hz, Ph-H), 7.74-7.76 (d, 2H, J=7.6 Hz, Ph-H), 12.99 (br,2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.06, 18.38, 24.49, 35.17,105.52, 121.20, 126.98 (2C), 128.37 (2C), 129.09, 129.29 (2C), 129.37,135.00, 136.08, 139.24, 143.40, 147.65, 153.06, 157.87, 160.77, 163.28.

Compound I-71 was prepared according to method for preparing the targetcompound I-1 except that 6-benzyl-5-ethyl-thiouracil A was used in theS-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 86%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.90-0.93 (t, 3H, J=7.3 Hz, CH₂—CH ₃), 2.42-2.48(m, 2H, CH ₂—CH₃), 3.90 (s, 2H, CH ₂-Ph), 4.43 (s, 2H, CH ₂—S),7.14-7.18 (t, 1H, J=7.0 Hz, Ph-H), 7.23-7.26 (t, 2H, J=7.3 Hz, Ph-H),7.28-7.30 (d, 2H, J=7.2 Hz, Ph-H), 7.40-7.44 (t, 1H, J=7.2 Hz, Ph-H),7.48-7.52 (t, 2H, J=7.4 Hz, Ph-H), 7.77-7.79 (d, 2H, J=7.6 Hz, Ph-H),12.86-13.43 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) δ 13.50, 18.68,24.48, 40.13, 105.67, 121.54, 126.65, 127.01 (2C), 128.74 (2C), 129.03,129.27 (4C), 138.96, 143.47, 146.32, 152.34, 156.96, 160.95, 163.79.

Compound I-72 was prepared according to method for preparing the targetcompound I-1 except that 6-(1′,3′-benzodioxy)-5-ethyl-thiouracil A wasused in the S-alkylation reaction of the step (6).

The product was obtained as a white crystal with a yield of 85%. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.91-0.94 (t, 3H, J=7.2 Hz, CH₂—CH ₃), 2.41-2.47(m, 2H, CH ₂—CH₃), 3.81 (s, 2H, CH ₂-Ph), 4.44 (s, 2H, CH ₂—S), 5.92 (s,2H, O—CH ₂—O), 6.74-6.79 (m, 2H, Ph-H), 6.85 (s, 1H, Ph-H), 7.40-7.44(t, 1H, J=7.2 Hz, Ph-H), 7.48-7.52 (t, 2H, J=7.4 Hz, Ph-H), 7.77-7.79(d, 2H, J=7.5 Hz, Ph-H), 12.83-13.43 (br, 2H, NH); ¹³C NMR (DMSO-d₆, 100MHz) δ 13.55, 18.61, 24.49, 39.69, 101.16, 105.18, 108.50, 109.65,122.18, 127.02 (2C), 129.02, 129.24 (2C), 131.14, 132.62, 144.38,146.07, 147.60, 151.33, 157.02, 160.58, 161.19, 163.59.

Effect Example 1: Anti-HIV-1 Activity Test

C8166 cells infected with HIV-1 were used for determining the anti-HIVbiological activity at the cellular level. The specific method wasdescribed below.

Cytotoxicity experiment: The toxicity of the compounds on C8166 cellswas determined by MTT method. In 96-well cell culture plates, thecompounds were subjected to 5-fold serial dilution and 100 μL of C8166cell suspension (4×10⁵/mL) was added into each well. Triplicate wellswere set for each concentration. At the same time, a cell control groupwithout drugs and drug control groups with Zidovudine (AZT) orNevirapine (NVP) were set. The cells were incubated at 37° C. in a 5%CO₂ incubator for three days, followed by the addition of MTT solutioninto each well, and then the cells were incubated at 37° C. for 4 hours.10% SDS-50% DMF was added into each well and the cells were incubated at37° C. in a 5% CO₂ incubator overnight. After mixing evenly, the ODvalues were measured by BIO-TEK ELx800 ELISA instrument (determinationwavelength: 570 nm; reference wavelength: 630 nm). The dose-responsecurve was graphed according to the experimental results, and the CC₅₀was calculated (the concentrations of the compounds required to producetoxicity on 50% cells).

Syncytium inhibition experiment: 100 μL of C8166 cell suspension(4×10⁵/mL) was seeded into each well of 96-well cell culture platescontaining 5-fold serial dilutions of the compounds, followed byaddition of HIV-1_(IIIB) diluted supernatant (MOI=0.04). Triplicatewells were set for each serial concentration. At the same time, negativecontrol wells of HIV-1_(IIIB) infection without compounds and positivecontrol wells with Zidovudine (AZT) or Nevirapine (NVP) were set. Thecells were cultured at 37° C. in a 5% CO₂ incubator for three days. Thenumber of the syncytia was counted in five non-overlapping fields ofview by using an inverted microscope (100×). The dose-response curveswere graphed according to the experimental results, and the 50%effective concentrations of the compounds for inhibiting the virus(EC50, 50% effective concentration) were calculated according to Reed &Muench method. Calculation formula: cytopathic inhibition rate(%)=(1−number of syncytia in experimental wells/number of syncytia incontrol well)×100%.

In the present disclosure, AZT and NVP were used as control, and theinhibitory activity data of some target compounds on HIV-1_(IIIB) isshown in Table 1:

TABLE 1 Inhibitory activity data of target compounds on HIV-1_(IIIB) No.CC₅₀ (μM) EC₅₀ (μM) SI I-01 >200 0.099 >2020.2 I-02 84.48 0.007 12069I-03 76.26 0.051 1495.3 I-04 58.06 0.101 574.85 I-05 80.99 0.066 1227.1I-06 66.08 0.057 1159.3 I-07 83.86 0.018 4658.9 I-08 74.93 0.020 3746.5I-09 64.92 0.018 3606.7 I-10 >200 0.023 >8695.7 I-11 49.84 0.130 383.38I-12 75.35 0.310 243.06 I-13 >200 0.349 >573.07 I-14 71.99 0.035 2056.9I-15 >200 0.071 >2816.9 I-16 >200 0.089 >2247.2 I-17 96.78 0.004 24195.0I-18 86.43 0.162 533.52 I-19 115.43 0.151 764.44 I-20 59.71 0.042 1421.7I-21 82.76 0.074 1118.4 I-22 >200 0.138 >1449.3 I-23 91.42 0.052 1758.1I-24 77.10 0.086 896.51 I-25 >200 0.012 >16666 I-26 34.42 0.302 113.97I-27 55.05 0.182 302.47 I-28 31.12 0.147 211.70 I-29 87.39 0.476 183.59I-30 67.93 0.296 229.49 I-31 75.01 0.033 2273.0 I-32 45.16 0.028 1612.9I-33 47.19 0.025 1887.6 I-34 79.44 0.023 3453.9 I-35 103.51 0.002 51755I-36 91.25 0.009 10139 I-37 72.96 0.006 12160 I-38 156.36 0.003 52120I-39 98.98 0.016 6186.3 I-40 >200 0.012 >16666 I-41 54.615 0.1864 339.5I-42 42.23 0.3551 134.7 I-43 66.88 0.1941 345.3 I-44 79.55 5.342 18.52I-45 61.62 10.07 6.75 I-46 56.05 3.956 14.16 I-47 61.77 0.142 436.23I-48 98.88 0.927 106.68 I-49 >200 0.837 >238.81 I-50 78.05 2.967 26.306I-51 45.54 0.602 75.660 I-52 >200 0.097 >2070.4 I-53 >200 0.141 >1415.4I-54 88.96 3.882 22.915 I-55 >200 0.700 >285.67 I-56 40.29 0.587 68.617I-57 81.09 0.080 1008.5 I-58 80.95 0.400 202.16 I-59 89.10 23.91 3.7259I-60 64.88 0.733 88.567 I-61 46.35 0.124 373.79 I-62 >200 4.980 >40.163I-63 >200 0.063 >3169.6 I-64 >200 0.643 >310.87 I-65 >200 0.370 >540.98I-66 >200 0.071 >2809.0 I-67 >200 0.847 >236.04 I-68 >200 0.111 >1802.6I-69 >200 0.055 >3656.3 I-70 >200 0.092 >2173.9 I-71 >200 0.051 >3940.9I-72 >200 0.081 >2470.7 AZT >749 0.049 >15286 NVP >200 0.0584 >3424

The compounds of the present disclosure are a novel structural type ofpyrimidinone-containing compounds. It can be seen from Table 1 that thecompounds have significant anti-HIV activities, the EC₅₀ values of someof the preferred compounds reach nanomolar levels, and the CC₅₀ valuesof compounds I-01, 10, 13, 15, 16, 22, 25, 40, 49, 52, 53, 55, 62-72 onC8166 cells are greater than 200 μM in vitro. Therefore, the compoundsof the present disclosure are novel HIV-RT inhibitors with novelstructures and have characteristics of high efficacy and low toxicity.

Although the specific embodiments of the present disclosure have beendescribed above, those skilled in the art should understand that theseembodiments are only intended for illustration, and various changes orvariations can be made to these embodiments without departing from thespirit and essence of the present disclosure. Therefore, the scope ofprotection of the present disclosure is defined by the appended claims.

1. A compound represented by formula I, or a N-oxide, tautomer, opticalisomer, hydrate, solvate, polymorph, pharmaceutically acceptable saltthereof or a prodrug thereof:

wherein: A is S, O, NH or NCH₃; R₁ is H, C₁-C₆ branched or straightchain alkyl, or C₃-C₆ cycloalkyl; R₂ is H or halogen; R₃ is H, C₁-C₁₂branched or straight chain alkyl, C₃-C₆ cycloalkyl, C₆-C₂₀ aryl, C₂-C₁₀heteroaryl, C₆-C₂₀ aryl substituted by one or more R_(3a), or C₂-C₁₀heteroaryl substituted by one or more R_(3b); wherein each of R_(3a) andR_(3b) is independently selected from hydroxyl, nitro, halogen, amino,cyano, HOS(═O)₂—, CH₃S(═O)₂—, C₁-C₆ branched or straight chainalkyl-S(═O)₂NH—, C₁-C₆ branched or straight chain alkyl, C₁-C₆ branchedor straight chain alkoxy, C₁-C₆ branched or straight chain alkylthio,C₁-C₆ branched or straight chain haloalkyl, when R_(3a) or R_(3b) ismore, then each R_(3a) or each R_(3b) is the same or different; α ringis cyclohexyl or phenyl, wherein the phenyl is substituted by n R₄ whereeach R₄ is the same or different, n is 0, 1, 2, 3 or 4; R₄ is halogen,hydroxyl, cyano, nitro, amino, C₁-C₆ branched or straight chain alkyl,or C₁-C₆ branched or straight chain alkoxy.
 2. The compound representedby formula I as defined in claim 1, wherein, when R₁ is C₁-C₆ branchedor straight chain alkyl, then the C₁-C₆ branched or straight chain alkylis C₁-C₃ branched or straight chain alkyl; when R₁ is C₃-C₆ cycloalkyl,then the C₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl; when R₂ is halogen, then the halogen is fluorine, chlorine,bromine or iodine; when R₃ is C₁-C₁₂ branched or straight chain alkyl,then the C₁-C₁₂ branched or straight chain alkyl is C₁-C₆ branched orstraight chain alkyl; when R₃ is C₃-C₆ cycloalkyl, then the C₃-C₆cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; whenR₃ is C₆-C₂₀ aryl substituted by one or more R_(3a), then the C₆-C₂₀aryl is C₆-C₁₀ aryl; when R₃ is C₂-C₁₀ heteroaryl substituted by one ormore R_(3b), then the C₂-C₁₀ heteroaryl is C₂-C₆ heteroaryl; when R_(3a)or R_(3b) is halogen, then the halogen is fluorine, chlorine, bromine oriodine; when R_(3a) or R_(3b) is C₁-C₆ branched or straight chainalkyl-S(═O)₂NH—, then the C₁-C₆ branched or straight chain alkyl isC₁-C₃ branched or straight chain alkyl; when R_(3a) or R_(3b) is C₁-C₆branched or straight chain alkyl, then the C₁-C₆ branched or straightchain alkyl is C₁-C₃ branched or straight chain alkyl; when R_(3a) orR_(3b) is C₁-C₆ branched or straight chain alkoxy, then the C₁-C₆branched or straight chain alkoxy is C₁-C₃ branched or straight chainalkoxy; when R_(3a) or R_(3b) is C₁-C₆ branched or straight chainalkylthio, then the C₁-C₆ branched or straight chain alkylthio is C₁-C₃branched or straight chain alkylthio; when R_(3a) or R_(3b) is C₁-C₆branched or straight chain haloalkyl, then the C₁-C₆ straight orbranched chain haloalkyl is C₁-C₃ straight or branched chain haloalkyl;when R₃ is phenyl substituted by one or more R_(3a), then thesubstituted is mono-substituted or di-substituted; when R₄ is halogen,then the halogen is fluorine, chlorine, bromine or iodine; when R₄ isC₁-C₆ branched or straight chain alkyl, then the C₁-C₆ branched orstraight chain alkyl is C₁-C₃ branched or straight chain alkyl; when R₄is C₁-C₆ branched or straight chain alkoxy, then the C₁-C₆ branched orstraight chain alkoxy is C₁-C₃ branched or straight chain alkoxy; when αring is phenyl substituted by n R₄ where each R₄ is the same ordifferent, then n is 2, all R₄ are halogen or all R₄ are C₁-C₆ branchedor straight chain alkyl; or, n is 2, the two R₄ are independently C₁-C₆branched or straight chain alkoxy.
 3. The compound represented byformula I as defined in claim 1, wherein, when R₁ is C₁-C₆ branched orstraight chain alkyl, then the C₁-C₆ branched or straight chain alkyl isisopropyl, n-propyl, ethyl or methyl; when R₂ is halogen, then thehalogen is chlorine; when R₃ is C₁-C₁₂ branched or straight chain alkyl,then the C₁-C₁₂ branched or straight chain alkyl is C₁-C₄ branched orstraight chain alkyl; when R₃ is C₆-C₂₀ aryl substituted by one or moreR_(3a), then the C₆-C₂₀ aryl is phenyl; when R₃ is C₂-C₁₀ heteroarylsubstituted by one or more R_(3b), then the C₂-C₁₀ heteroaryl ispyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrimidinonyl, oxadiazolyl, pyridonyl or triazolyl; when R_(3a) orR_(3b) is C₁-C₆ branched or straight chain alkyl-S(═O)₂NH—, then theC₁-C₆ branched or straight chain alkyl is methyl, ethyl, n-propyl orisopropyl; when R_(3a) or R_(3b) is C₁-C₆ branched or straight chainalkyl, then the C₁-C₆ branched or straight chain alkyl is methyl, ethyl,n-propyl or isopropyl; when R_(3a) or R_(3b) is C₁-C₆ branched orstraight chain alkoxy, then the C₁-C₆ branched or straight chain alkoxyis methoxy, ethoxy, propoxy or isopropoxy; when R_(3a) or R_(3b) isC₁-C₆ branched or straight chain alkylthio, then the C₁-C₆ branched orstraight chain alkylthio is methylthio, ethylthio, propylthio orisopropylthio; when R_(3a) or R_(3b) is C₁-C₆ branched or straight chainhaloalkyl, then the C₁-C₆ straight or branched chain haloalkyl istrifluoromethyl, difluoromethyl or 1,2-difluoroethyl; when R₃ is phenylsubstituted by one or more R_(3a), the substituted is mono-substituted,then the mono-substituted is 3-substituted or 4-substituted; when thesubstituted is di-substituted, then the di-substituted is2,4-di-substituted or 3,4-di-substituted; when R₄ is C₁-C₆ branched orstraight chain alkyl, then the C₁-C₆ branched or straight chain alkyl ismethyl, ethyl, n-propyl or isopropyl; when R₄ is C₁-C₆ branched orstraight chain alkoxy, then the C₁-C₆ branched or straight chain alkoxyis methoxy, ethoxy, propoxy or isopropoxy; when α ring is phenylsubstituted by n R₄ where each R₄ is the same or different, n is 2, allR₄ are halogen or all R₄ are C₁-C₆ branched or straight chain alkyl,then all R₄ are fluorine, or all R₄ are chlorine, or all R₄ are methyl;or, n is 2, the two R₄ are C₁-C₆ branched or straight chain alkoxy, thenthe two R₄ are linked together to form α ring, where the ring is anoxygen-containing heterocycle fused to the phenyl.
 4. The compoundrepresented by formula I as defined in claim 1, wherein, when R₃ isC₁-C₁₂ branched or straight chain alkyl, then the C₁-C₁₂ branched orstraight chain alkyl is methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, sec-butyl or tert-butyl; when R₃ is C₆-C₂₀ aryl substituted byone or more R_(3a), then the C₆-C₂₀ aryl substituted by one or moreR_(3a) is

when α ring is phenyl substituted by n R₄ where each R₄ is the same ordifferent and n is 2, then R₄ is located in the 2-position and6-position of the phenyl, or 3-position and 5-position of the phenyl;when α ring is phenyl substituted by n R₄ where each R₄ is the same ordifferent and n is 2, the two R₄ are linked together to form anoxygen-containing heterocycle fused to the phenyl, then the two R₄ forman oxygen-containing 5-7 membered heterocycle fused to the phenyl. 5.The compound represented by formula I as defined in claim 1, wherein, Ais S; and/or, α ring is

and/or, R₁ is H, methyl, ethyl or isopropyl; and/or, R₂ is H or Cl;and/or, R₃ is C₆-C₂₀ aryl, C₂-C₁₀ heteroaryl, C₆-C₂₀ aryl substituted byone or more R_(3a), or C₂-C₁₀ heteroaryl substituted by one or moreR_(3b).
 6. The compound represented by formula I as defined in claim 1,wherein, when R₃ is C₆-C₂₀ aryl substituted by one or more R_(3a), orC₂-C₁₀ heteroaryl substituted by one or more R_(3b), then the one ormore is 1-6, 1-3 or 1-2.
 7. The compound represented by formula I asdefined in claim 1, wherein, A is S, α ring is

R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is C₆-C₂ aryl, C₂-C₁₀heteroaryl, C₆-C₂₀ aryl substituted by one or more R_(3a), or C₂-C₁₀heteroaryl substituted by one or more R_(3b); or, A is S, α ring is

R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is phenyl or phenylsubstituted by one R_(3a), wherein R_(3a) is hydroxyl, halogen, C₁-C₆branched or straight chain alkoxy or C₁-C₆ branched or straight chainalkylthio; the substituted is 4-substituted; or, A is S, α ring iscyclohexyl, R₁ is ethyl or isopropyl; R₂ is H or Cl; R₃ is phenyl orphenyl substituted by one R_(3a), wherein R_(3a) is hydroxyl, F, Cl,methoxy or methylthio; the substituted is 4-substituted.
 8. The compoundrepresented by formula I as defined in claim 1, wherein, the moiety

contained in the compound represented by formula I is


9. The compound represented by formula I as defined in claim 1, wherein,the compound is selected from the group consisting of: CompoundStructure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72


10. A method for preparing a compound represented by formula I,comprising carrying out an alkylation reaction of intermediate 6 andintermediate 7 in the presence of a base in a solvent;

wherein the definitions of A, n, R₁, R₂, R₃, R₄ and α ring are asdefined in claim 1, X is halogen.
 11. The method for preparing thecompound represented by formula I as defined in claim 10, wherein themethod further comprises carrying out a halogenation reaction ofintermediate 5 with a halogenating agent in a solvent to obtain theintermediate 6;

wherein the definitions of R₂ and R₃ are as defined in claim 10, X ishalogen.
 12. The method for preparing the compound represented byformula I as defined in claim 11, wherein the method further comprisescarrying out a reduction reaction of intermediate 4 in the presence of areducing agent in a solvent to obtain the intermediate 5;

wherein the definitions of R₂ and R₃ are as defined in claim
 11. 13. Themethod for preparing the compound represented by formula I as defined inclaim 12, wherein the method further comprises carrying out ahalogenation reaction of intermediate 3 with a halogenating agent in asolvent to obtain the intermediate 4;

wherein the definitions of R₂ and R₃ are as defined in claim
 12. 14. Amethod for inhibiting non-nucleoside HIV-1 in a subject in need thereof,comprising administering a therapeutically effective amount of thecompound represented by formula I, or the N-oxide, tautomer, opticalisomer, hydrate, solvate, polymorph, pharmaceutically acceptable saltthereof or the prodrug thereof as defined in claim 1 to the subject. 15.The method as defined in claim 14, wherein the non-nucleoside HIV-1 isnon-nucleoside HIV-1_(IIIB).
 16. A method for treating and/or preventinghuman immunodeficiency virus infection in a subject in need thereof,comprising administering a therapeutically effective amount of thecompound represented by formula I, or the N-oxide, tautomer, opticalisomer, hydrate, solvate, polymorph, pharmaceutically acceptable saltthereof or the prodrug thereof as defined in claim 1 to the subject. 17.A pharmaceutical composition, comprising a therapeutically effectiveamount of the compound represented by formula I, or the N-oxide,tautomer, optical isomer, hydrate, solvate, polymorph, pharmaceuticallyacceptable salt thereof or the prodrug thereof as defined in claim 1,and at least one pharmaceutical excipient.
 18. A method for treatinghuman immunodeficiency virus infection disease, comprising administeringa therapeutically effective amount of the compound represented byformula I, or the N-oxide, tautomer, optical isomer, hydrate, solvate,polymorph, pharmaceutically acceptable salt thereof or the prodrugthereof as defined in claim 1 to a subject in need thereof.